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.

Fig. 1

Proportion of individuals for 3 common causes of acquired epilepsy, traumatic brain injury (TBI), stroke, and status epilepticus who develop epilepsy and the contribution of these conditions to the overall burden of epilepsy. To prevent epilepsy due to status epilepticus (A) or TBI (C), patients (F or D, respectively) would need to be treated with an anti-epileptogenic drug after the insult. For patients who have TBI, the rates of subsequent epilepsy are low (C and D is approximately 10 % for all moderate-to-severe TBI at 3 years [46]) and the majority of individuals exposed to anti-epileptogenic treatment would not have developed epilepsy anyway. In this case, the number needed to treat (NNT) to prevent 1 case of epilepsy is high. In contrast, a higher proportion of patients develop epilepsy after status epilepticus (A and F is approximately 68 % [47]). The number of patients with status epilepticus exposed to an anti-epileptogenic drug to prevent on case of epilepsy is much lower. However, the effect of preventing epilepsy due to status epilepticus on the overall incidence of epilepsy is relatively low because it is a rare cause of epilepsy (A = 3 %). Finally, the proportion of individuals who develop epilepsy after a stroke (B, E) is also relatively low and the NNT to prevent 1 case of post-stroke epilepsy if all patients who present after a stroke are treated would be high. However, if a biomarker identified after stroke associated with onset of epileptogenesis (shown in the schematic in yellow) can be used to select patients for anti-epileptogenic treatment, the NNT to prevent post-stroke epilepsy could be reduced significantly

Fig. 2

Schematics for possible design of epilepsy prevention trials. (A) For an epileptogenic insult with a short latent period for the onset of epilepsy, participants could be randomized to receive anti-epileptogenic (AEG) treatment or control (standard anti-seizure treatment or placebo) for a period of time after the insult. Participants would be followed for the onset of seizures during and after the treatment period. If anti-epileptogenic treatment is effective, the rate of developing unprovoked seizures would be lower in the AEG-treated group. (B) For an insult associated with a long latent period, the observation period could be delayed and participants could be assessed for seizure occurrence months to years after the insult provided few individuals are lost to follow-up during the delay. (C) An alternate strategy to demonstrate the disease-modifying properties of an experimental treatment is a delayed start design where participants are randomized to receive AEG treatment early after an insult or after some delay and then observed following the discontinuation of therapy. If the experimental treatment is truly disease-modifying, the proportion of participants who develop epilepsy will be higher in the late-treated group and early-treatment group will never “catch up” at the end of the observation period. A third comparison group that received standard anti-seizure drug or placebo could be employed to improve the internal validity of the study

Fig. 3

Schematics for possible design of disease modification trials in ongoing epilepsy. To assess a compound for its ability for disease modification, patients with epilepsy could be randomized to receive disease modification (DM) treatment or control (standard anti-seizure treatment) for a period of time. Patients would be followed for change of the chosen parameter, for example entering seizure remission (A) or change in seizure frequency (B) during DM treatment and following DM treatment withdrawal. If DM is effective, the rate of seizures would be lower in the DM group. The observation period could be prolonged and patients could be assessed for seizure occurrence months to years after the treatment provided enough patients are remaining in follow-up. If the experimental treatment is truly disease-modifying, the proportion of patients in remission will be higher at the end of the observation period