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Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, AustraliaDepartment of Neurology, Royal Melbourne Hospital, Parkville, Australia
Despite the exponential growth of approved antiepileptic drugs (AEDs) over the past 25 years, epilepsy remains uncontrolled in approximately a third of patients. This article summarises the clinical trials and properties of the AEDs developed over this period, and reviews the pre-clinical and clinical development paradigms of modern AEDs. We discuss possible reasons for the apparent failure to develop more efficacious compounds. We also review the current regulatory frameworks for drug approval in the United States and Europe, and the changes on the horizon. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning pharmacoresistance and the epilepsies by recent research has enabled a revised approach to the development of more promising therapies. A new era of pharmacological treatment for epilepsy appears imminent. Future research in pharmacotherapy for drug-resistant epilepsy will be advanced through concerted effort between scientists, clinicians, and the industry.
The mainstay of treatment for epilepsy is pharmacological therapy for seizure control. Driven by the limited efficacy of the established antiepileptic drugs (which generally include carbamazepine, ethosuximide, phenobarbital, phenytoin and valproic acid), antiepileptic drug (AED) development has exploded in the past 25 years (Fig. 1). But despite the release of a new agent almost annually over this period, epilepsy remains uncontrolled in one third of patients [
]. Uncontrolled epilepsy is associated with poorer quality of life, increased physical and psychological comorbidities, and increased risk of sudden unexplained death in epilepsy, placing substantial burden on the individuals, carers, and society [
This article reviews the pre-clinical and clinical development paradigms of modern AEDs, and summarises the clinical trials and properties of the newer AEDs approved for the treatment of drug-resistant epilepsy over the past 25 years. We discuss possible reasons for the lack of fundamental improvement in treatment efficacy, and provide an overview of promising research directions in pharmacotherapy for drug-resistant epilepsy.
2. Preclinical drug development paradigms
Three main approaches have been employed to identify compounds with potential anti-seizure activity: random screening of synthesized chemicals, structural variations of known AEDs, and rational drug development through selective targeting of seizure-inducing mechanisms [
]. All approaches rely on the preclinical use of animal models to establish safety and efficacy of the investigational compounds prior to human trials. The maximal electric shock (MES) and the subcutaneous pentylenetetrazol (scPTZ) rodent models have traditionally been the first-line models for the discovery of new AEDs. In the MES model, seizures are induced by bilateral trans-auricular or corneal electrical stimulation. The model tends to identify drugs that block generalized tonic-clonic seizures [
]. However, several newer AEDs (such as vigabatrin and levetiracetam) with demonstrated efficacy for focal seizures in human epilepsy are ineffective in the MES model. In the scPTZ model, clonic seizures are evoked through subcutaneous administration of convulsant doses of PTZ, which acts as a GABAA receptor antagonist [
]. The scPTZ model tends to identify drugs that block generalized non-convulsive (myoclonic, absence) seizures.
The MES and scPTZ models have proven useful for detecting anti-seizure effects of drugs in healthy rodents, and have provided insight into the pharmacokinetic and pharmacodynamic interactions of potential AEDs [
]. However, both models can produce false negative results, the notable example being levetiracetam. Importantly, these acute seizure models are not designed to identify compounds which act to inhibit spontaneous seizures or drug-resistant epilepsy [
]. Since chemicals not effective in these models are excluded from further development, this is of significant concern. The diversity of human epilepsy syndromes poses a need for animal models that more fully capitulate the clinical scenarios.
To address this need, other animal models have recently been developed to supplement the MES and scPTZ tests [
]. These include the 6 Hz psychomotor seizure model, phenytoin-resistant kindled rat, lamotrigine kindled-rat, post-status epilepticus models of temporal lobe epilepsy, and the methylazozymethanol (MAM) model [
]. In particular, the 6 Hz test has been readily adopted in the National Institutes of Health AED discovery program. This model administers low-frequency and long-duration electrical stimulation via corneal electrodes to induce focal seizures [
]. The kindling model aims to mimic the development of focal epilepsy through repeated applications of subthreshold electrical stimulations to specific brain regions (usually the amygdala or hippocampus) to induce increasingly severe seizure behaviour. It has been noted, however, that AEDs which exhibit high efficacy in the kindling model do not necessarily have higher clinical efficacy in patients with drug-resistant focal seizures.
3. Limitations of animal models in AED development
The MES and scPTZ preclinical models have proven useful for identifying various new AEDs, but they have not resulted in the development of AEDs with higher efficacy than established agents in drug-resistant patients. This is likely due to the intrinsic limitations of these models. First, seizure definitions used in experimental animal models are limited to specific convulsive phenotypes and minimum durations, and fail to account for the short non-convulsive seizures often observed in human focal epilepsies. Second, these pre-clinical models were originally validated by the older AEDs, which may explain the failure to identify novel AEDs with better efficacy and tolerability [
]. This contributes to the redundancy of “me-too” drugs. Third, the determination of drug efficacy is dependent upon the ability of an investigational drug to inhibit provoked seizures, whereas the seizures in human epilepsy are characteristically unprovoked and originate from a molecular substrate. However, it has been observed that the pharmacology of the provoked seizures in the kindling model and the spontaneous seizures in the post-status epilepticus model is similar, suggesting that the model’s brain alterations may be more important than the method of seizure induction [
Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs: a comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy.
Due to ethical reasons, investigational compounds are initially tested as adjunctive treatment in patients with uncontrolled epilepsy. Similar paradigms have been adopted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical AED development. Generally speaking, a new molecular agent is required to undergo at least two independent studies before regulatory submission can be accepted for approval. Regulatory trials are randomized, double-blind and placebo-controlled, and usually evaluate a number of fixed doses [
]. A Phase III trial typically includes a baseline period, a titration period and a maintenance period. The titration period involves increasing the dose of the drug up to the maximal tolerated dose, or a pre-defined fixed dose, which is maintained for usually 12–16 weeks. Although there is no regulatory guidance regarding forced or flexible dose titration, both the FDA and EMA prefer pre-defined target doses, covering the purportedly minimal effective dose to the maximal tolerated dose [
]. Phase III programs often include an open label extension phase to assess long-term safety and seizure outcomes.
There are minor differences in the primary efficacy outcome measure accepted by the agencies: the EMA prefers responder rate (percentage of patients with at least 50% reduction in seizure frequency during the treatment phase compared with the baseline), while the FDA requires outcomes to be measured as median percent seizure reduction.
Table 1 summarizes the phase III clinical trials that evaluated investigational AEDs in the past 25 years. The pharmacological properties of the AEDs approved in this period are provided in Table 2 [
Table 1Summary of double-blind, randomized phase III trials of antiepileptic drugs for treatment of refractory partial (focal) onset seizures (+/− other seizure types).
Drug
Seizure type
Study design (number of trials performed)
Total population (number of patients in active arm(s))
Comparator
Primary outcome measure
Reference(s)
Vigabatrin
Partial onset
Adjunctive, cross-over (n = 3)
n = 23 (n = 23); n = 31 (n = 31); n = 97 (n = 97)
Placebo
Decrease in total number of seizures; percent change in mean weekly seizure frequency; monthly seizure rate, calculated for each of the four-week study periods
Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.
Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 82/83.
Gabapentin monotherapy: I. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 88/89.
n = 181 (n = 136); n = 47 (n = 23); n = 41 (n = 20)
Placebo
Percent reduction in average monthly seizure rate; (1) median percent seizure reduction (2) ≥50% reduction; proportion of patients with ≥50% seizure reduction
Proportion of responders (patients achieving a reduction of 50% or more in the 4-weekly seizure rate) calculated for all partial seizures and for each seizure subtype; median change in 4-week seizure frequency
A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group.
n = 294 (n = 199); n = 324 (n = 212); n = 56 (n = 28)
Placebo
Mean number of partial seizures per week; weekly partial seizure frequency; logarithmically transformed weekly frequency of partial seizures over the 16-week, double-blind treatment phase
Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group.
Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group.
Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study.
n = 453 (n = 353); n = 287 (n = 191); n = 313 (n = 225); n = 341 (n = 268); n = 178 (n = 119)
Placebo
Reduction in seizure frequency as measured by RRatio; reduction in seizure frequency during treatment as compared to baseline; change in seizure frequency from baseline; reduction in seizure frequency as measured by RRatio; reduction in seizure frequency as measured by RRatio
Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study.
Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial.
n = 497 (n = 421); n = 485 (n = 318); n = 405 (n = 301)
Placebo
(1) change in seizure frequency per 28 days from baseline to maintenance (2) reduction of at least 50% in seizure frequency from baseline to maintenance
Conversion-to-monotherapy, historical control (n = 1)
n = NA (n = 425)
Historical pseudo-placebo
Kaplan–Meier-predicted percentage of patients on 400 mg/day in the full analysis set meeting ≥ 1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold
Efficacy and safety of adjunctive lacosamide for the treatment of partial-onset seizures in Chinese and Japanese adults: a randomized, double-blind, placebo-controlled study.
Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study.
Kaplan–Meier-estimated 112-day exit rate with a threshold value calculated from the historical controls; proportion of patients meeting predefined exit criteria
Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America.
Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.
Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
Partial onset
Adjunctive (n = 4)
n = 399 (n = 303); n = 538 (n = 359); n = 305 (n = 153); n = 75 (n = 50)
Placebo
Percentage change from baseline in monthly seizure frequency and compared across treatment arms; change in 28-day seizure frequency; (1) percent change in 28-day total partial-seizure frequency from baseline to 18-week double-blind period (2) responder rate, defined as the proportion of patients experiencing a ≥50% reduction in 28-day total partial-seizure frequency from baseline to maintenance phase; proportion of responders, defined as patients with ≥50% reduction in 28-day total partial-onset seizure frequency, from the baseline phase to the maintenance phase
Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: a randomized, placebo-controlled phase III study.
Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
Partial onset
Adjunctive (n = 4)
n = 387 (n = 266); n = 706 (n = 521); n = 386 (n = 250); n = 162 (n = 81)
Placebo
The responder rate (percentage of patients who experienced a 50% reduction in seizure frequency in the maintenance period relative to baseline); median percent change in seizure frequency; (1) percent change in 28-day total partial-seizure frequency from baseline to 18-week double-blind period (2) responder rate, defined as the proportion of patients experiencing a ≥50% reduction in 28-day total partial-seizure frequency from baseline to maintenance phase; Percent change in PGTC seizure frequency
Approved for adjunctive use only; RRatio=(T−B)/(T+B), where T and B are the seizure frequencies during treatment and during baseline.
Partial onset
Adjunctive (n = 4)
n = 396 (n = 298); n = 480 (n = 359); n = 398 (n = 298); n = 768 (n = 501)
Placebo
Focal seizure frequency per week; median percent reduction in baseline-adjusted seizure frequency; focal seizure frequency per week; (1) percent reduction in 28-day adjusted partial onset seizure frequency (2) ≥50% responder rate based on percent reduction in seizure frequency from baseline to the treatment period
A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures.
Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial.
Following the approval of an AED as adjunctive therapy, its further development for monotherapy use is under different regulatory frameworks in the US and Europe. The FDA requires that trials show superiority of the investigational drug over a comparator agent. However, randomizing patients to placebo has ethical concerns. Several new study designs were developed to comply with this regulation, but were eventually abandoned for ethical reasons. These included the once widely implemented “pseudo-placebo” design, in which a small dose of a single agent is given to patients in one arm [
In contrast to the FDA, the EMA accepts direct comparison of a new drug with an existing drug. In this paradigm, demonstration of equivalence or non-inferiority is adequate for approval. Several drugs have gained monotherapy approval using the non-inferiority design, including levetiracetam [
Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.
], which both used a flexible-dosing design and controlled-release carbamazepine as the comparator. The main concern with non-inferiority designs, and the reason why the FDA requires a superiority outcome, is their unproved assay sensitivity. This is based on the argument that equivalent efficacy in the two trial arms could have been similarly achieved by a placebo.
4.3 The historical-control design
In the US, monotherapy efficacy assessment in drug-resistant patients had traditionally employed either “withdrawal-to-monotherapy” or “withdrawal-to-placebo.” These approaches have raised ethical concerns and may not adequately reflect intended use, and have thus attracted widespread criticism [
]. In this approach, drug-resistant patients are withdrawn to the study drug in monotherapy, and compared to a historic control group modelled from previous conversion-to-monotherapy study data. This design has been adopted for evaluating monotherapy indication of eslicarbazepine acetate, lacosamide, lamotrigine extended release, levetiracetam extended release and pregabalin [
Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study.
Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America.
]. However, this design has inherent concerns relating to the inconsistency between study cohorts and time-dependent population changes. Additionally, the lack of a parallel control group prevents effective blinding of treatment (some trials used blinded doses). For these reasons, the EMA regards historical-control studies as complementary rather than conclusive for the assessment of monotherapy indication [
4.4 Should separate monotherapy indication be re-examined?
To expedite monotherapy approval, Mintzer et al. recently proposed re-examination of the policy of separate approvals for AEDs as monotherapy and adjunctive therapy [
]. It is noted that AEDs are the only neurotherapeutics with separate indications for monotherapy and adjunctive use, which creates complications to the approval process. They suggest that regulatory restrictions that prevent or delay monotherapy approval for valuable new drugs is harmful to patients (for example, levetiracetam is not granted monotherapy indication in the US). They propose that AEDs should be approved for the treatment of specific seizure types, with approval for monotherapy and adjunctive use granted simultaneously. Whether the FDA can be persuaded remains to be seen. However, sequential licensing has recently been accepted by the EMA [
]. The AED under examination would be approved for adjunctive and second-intention monotherapy use, and then granted unrestricted monotherapy license after successfully adhering to a series of safety checkpoints. No monotherapy AED approval has been granted under these new pathways yet.
5. Future research directions
Despite the introduction of over 15 new compounds in the past 25 years, the overall proportion of patients with refractory epilepsy has remained largely unchanged. A shift from symptomatic seizure control to targeting underlying biological mechanisms is needed. The transition towards the development of disease-modifying treatments would be accelerated by a better understanding of the heterogeneous nature of epilepsy and the multiple complex factors that contribute to the abnormal neural discharges. Table 3 lists selected new compounds currently under early clinical investigation.
Table 3Selected compounds currently under clinical investigation.
Developmental approach
Name of compound
Mechanism of action
References
Mechanisms of action similar to those of marketed AEDs
Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model.
5.1 Promising approaches for pharmacological therapy
There is a need to elucidate the pathology underpinning pharmacoresistance to develop novel therapies. Several hypotheses have been formulated. These include the target hypothesis, the multidrug transporter hypothesis and the network hypothesis [
]. The target hypothesis suggests that alteration of molecular drug targets results in reduced response to treatment. This hypothesis is based on studies of AED effects on hippocampal voltage-gated sodium channels [
]. The multidrug transporter hypothesis postulates that an overexpression of efflux transporters at the blood–brain barrier restricts penetration of AEDs and reduces drug concentrations to subtherapeutic levels. Bankstahl et al. addressed this hypothesis by determining the efficacy of six AEDs in wildtype mice and mice deficient in P-glycoprotein (Pgp), one of the best studied efflux transporters, in a kainate-induced status epilepticus model of mesial temporal lobe epilepsy [
]. No significant differences in anti-seizure drug efficacies were observed between wildtype and Pgp-deficient mice. While this finding does not invalidate the multi-drug transporter hypothesis, it suggests that Pgp may not be functionally relevant in the mechanisms underlying drug resistant seizures. The co-administration of transporter inhibitors with AEDs is a promising therapeutic avenue to overcome drug resistance, but further research into other efflux transporters is needed. The network hypothesis suggests that neurodegeneration occurs in drug-resistant brains, and postulates that drugs with neuroprotective actions may be beneficial. Stemming from this hypothesis, immunosuppressive treatments and inhibitors of inflammation have been considered as potential therapeutic options. They include inhibitors of cytokine synthesis, neuro-immunophilins, corticosteroids and interleukin-1 receptor antagonists [
Glia-neuronal interactions in ictogenesis and epileptogenesis: role of inflammatory mediators.
in: Noebels J.L. Avoli M. Rogawski M.A. Olsen R.W. Delgado-Escueta A.V. Jasper’s Basic Mechanisms of the Epilepsies. National Center for Biotechnology Information (US),
Bethesda, MD2012
Agents with disease-modifying effects are of emergent interest in epilepsy treatment research. Although evidence for anti-epileptogenic effect of approved AEDs (including levetiracetam, phenobarbital, valproate and topiramate) is present in the post-status epilepticus animal models, this property has not been demonstrated in humans. These models have also been employed to screen for disease-modifying effects of non-AED compounds. Lorsartan is an example of such a compound, and has been shown to inhibit epileptogenic mechanisms in vivo [
]. Rapamycin and derivative molecules (everolimus, temsirolimus, deforolimus, ridaforolimusm) inhibit the mTOR signalling system and represent another potential class of epileptogenic compounds. They have been explored in animal models of tuberous sclerosis complex and some models of acquired epilepsy, and display promising results in human trials of tuberous sclerosis complex [
The blood–brain barrier is also under investigation as a possible target. Agents such as doxycline and minocycline that affect blood–brain barrier permeability are potential anti-epileptogenic candidates. Other compounds that have been of emerging interest are anti-apoptotic agents (such as corticotropin releasing hormone, and some AEDs), antioxidants (lipoic acid, adenosine, melatonin, vitamins C and E) and activators of neurotrophic receptors (fibroblast growth factor 2, brain derived neurotrophic factor, neuropeptide Y, inhibitors of TrkB kinase, erythropoietin) [
]. Interestingly, cannabidiol’s anti-seizure properties are not mediated by an interaction with cannabinoid receptors, despite its structural similarity to tetrahydrocannabinol [
]. Pre-clinical evaluations have confirmed these properties, and cannabidiol is now being subject to various clinical trials. In addition to its potential as an anti-seizure agent, cannabidiol has been shown to possess neuroprotective and anti-inflammatory effects. Promising results were found in a recently completed open-label study investigating the use of cannabidiol oral solution as an adjunctive therapy for paediatric and adult patients with drug-resistant epilepsy [
]. A number of randomized controlled trials are underway to elucidate the efficacy and safety profile of cannabidiol.
5.2 Precision medicine
Individual response to pharmacological treatment is influenced by the genetic profile. Pharmacogenomics is a new addition to epilepsy research, offering the potential to personalise treatment for individuals with epilepsy. The EMA defines pharmacogenomics as the “study of the variability of individual genes relevant to disease susceptibility as well as drug response at cellular, tissue, individual or population level” [
]. Taking this approach further, precision medicine aims to stratify individuals into subpopulations based on differences in disease susceptibility, prognosis and treatment response. Precision medicine thus promises to maximise outcomes and minimise unnecessary adverse drug reactions and expenditure, providing clinical and socioeconomic benefits for both the individual patients and the community. A battery of genetic tests is currently used for screening epilepsy susceptibility genes and to characterize gene variant profiles at the family and population level. It is proposed that by identifying the causative mutation for an individual epilepsy case, targeted therapeutic choices can be made. Under this paradigm, clinical practice will no longer be directed by the suboptimal “trial and error” methods.
The repurposing of existing drugs not currently indicated for epilepsy has the potential to overcome drug resistance. Personalized genomic medicine was successfully implemented in the diagnosis and treatment in a recent case of drug-resistant infantile-onset epilepsy [
]. A novel mutation was found in the GRIN2A gene, coding for the NMDA receptor (which has a pivotal role in neuronal communication). Following administration of the Alzheimer disease drug memantine, which reduces chronic overstimulation of NMDAR, a reduction in seizure frequency was observed. Another important example of drug repositioning in precision medicine is the use of quinidine. Case reports show that this cardiac anti-arrhythmia drug is effective in epilepsy syndromes with an underlying gain-of-function mutation in the KCNT1 gene [
]. Quinidine inhibits the KCNT1 sodium-activated potassium channel, encoded by the KCNT1 gene. It is hypothesized that quinidine may counteract the effect of the mutation of the channel.
6. Conclusion
While the lack of substantial progress of treatment for drug-resistant epilepsy over the past two decades has been attributed to deficiencies in the preclinical and clinical stages of development, there is a sense that a new era of treatment for drug-resistant therapy is imminent. A better understanding of the underlying physiological mechanisms leading to epilepsy has permitted the move towards developing novel target-driven therapeutic strategies [
]. This may allow optimization of the translation of preclinical findings to clinical research through thorough validation of novel drug-targets prior to extensive drug discovery work. The multifactorial mechanisms underpinning drug resistance will continue to demand collective effort from basic science and clinical research.
Conflict of interest statement
PK has received research grants from the National Health and Medical Research Council of Australia, the Australian Research Council, RMH Neuroscience Foundation, the US National Institutes of Health, Bill & Melinda Gates Foundation, Hong Kong Research Grants Council, Innovation and Technology Fund, Health and Health Services Research Fund, and Health and Medical Research Fund. He/his institution also received speaker or consultancy fees and/or research grants from Eisai, GlaxoSmithKline, Johnson & Johnson, Pfizer, and UCB Pharma.
Acknowledgement
AG is supported by the University of Melbourne Chancellor’s Scholars Program.
Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs: a comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy.
Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial.
Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: a double-blind, randomised, multicentre, historical control study.
Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a randomized historical-control phase III study based in North America.
Glia-neuronal interactions in ictogenesis and epileptogenesis: role of inflammatory mediators.
in: Noebels J.L. Avoli M. Rogawski M.A. Olsen R.W. Delgado-Escueta A.V. Jasper’s Basic Mechanisms of the Epilepsies. National Center for Biotechnology Information (US),
Bethesda, MD2012
Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group.
Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 82/83.
Gabapentin monotherapy: I. An 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 88/89.
A double-blind, placebo-controlled trial of tiagabine given three-times daily as add-on therapy for refractory partial seizures. Northern European Tiagabine Study Group.
Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group.
Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group.
Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study.
Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial.
Efficacy and safety of adjunctive lacosamide for the treatment of partial-onset seizures in Chinese and Japanese adults: a randomized, double-blind, placebo-controlled study.
Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel-group phase III study.
Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.
Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: a randomized, placebo-controlled phase III study.
A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures.
Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial.
Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model.
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