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Anti-epileptogenic clinical trial designs in epilepsy: issues and options.

ABSTRACT: Although trials with anti-seizure drugs have not shown anti-epileptogenic or disease-modifying activity in humans, new compounds are on the horizon that may require novel trial designs. We briefly discuss the unique challenges and the available options to identify innovative clinical trial designs that differentiate novel anti-epileptogenic and disease-modifying compounds, preferably early in phase II, from current anti-seizure drugs. The most important challenges of clinical testing of agents for epilepsy prevention include having sufficient preclinical evidence for a suitable agent to proceed with a human trial of an anti-epileptogenic drug, and to demonstrate the feasibility of doing such a trial. Major challenges in trial design to assess agents for disease modification include the choice of suitable study parameters, the identification of a high-risk study population, the type of control, the time and duration of treatment, and a feasible follow-up period.

SUBMITTER: Schmidt D

PROVIDER: S-EPMC3996121 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Anti-epileptogenic clinical trial designs in epilepsy: issues and options.

Schmidt Dieter D Friedman Daniel D Dichter Marc A MA

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20140401 2

Although trials with anti-seizure drugs have not shown anti-epileptogenic or disease-modifying activity in humans, new compounds are on the horizon that may require novel trial designs. We briefly discuss the unique challenges and the available options to identify innovative clinical trial designs that differentiate novel anti-epileptogenic and disease-modifying compounds, preferably early in phase II, from current anti-seizure drugs. The most important challenges of clinical testing of agents f ...[more]

PMID: 24420312

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Project description:Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs ("precision medicine") for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome.

Dataset Information

Anti-epileptogenic clinical trial designs in epilepsy: issues and options.

Publications

Anti-epileptogenic clinical trial designs in epilepsy: issues and options.

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