Adjunctive clinical trials in epilepsy: is a placebo arm necessary?

One of the fundamental questions that needs to be answered when evaluating an investigational drug in randomized clinical trials is whether the study drug demonstrated efficacy for the condition under evaluation. For patients with epilepsy, clinical trials are initially conducted to assess the efficacy of the investigational agent when administered as adjunctive therapy. This design is derived from ethical concerns that argue against exposing patients with epilepsy to a study drug as monotherapy without some evidence of efficacy. Once efficacy is demonstrated in adjunctive clinical trials, the study drug can be subsequently evaluated in monotherapy trials. The design of add-on clinical trials in patients with localization-related epilepsy has been relatively uniform. Eligible patients are those with medically refractory partial-onset seizures and experiencing a minimum number of monthly seizures (typically four or more seizures/month), while maintaining constant doses of one to three antiepileptic drugs (AEDs). Following a prospective baseline phase of approximately 8 weeks, patients still satisfying the entry criteria and with the required number of seizures are randomized in a doubleblind fashion to add-on treatment with the study drug (at one or multiple daily doses) or to add-on placebo in addition to constant doses of their baseline AEDs. The double-blind period, which consists of a titration and a maintenance phase, typically lasts 12–16 weeks. The primary efficacy variable is the change in seizure frequency during the double-blind period compared to baseline between the study drug and the placebo. A relatively large number of such trials were conducted over the past 15 years and were successful in demonstrating the efficacy of a number of newer AEDs, including felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and vigabatrin. The availability of such a number of trials of relatively consistent design allows for the opportunity to reconsider if a placebo arm is actually needed in adjunctive clinical trials for patients with medically refractory localization-related epilepsy or whether placebo can be established as a historical control. An argument could be made that a placebo arm in such trials would not be needed if one of two requirements were satisfied. The first would be a ‘‘consistent’’ finding of a negligible placebo effect (e.g., a minimal reduction of seizure frequency of 5% or less for the placebo arm) across clinical trials of similar designs. The other would be a ‘‘homogeneous’’ treatment effect for patients randomized to placebo. For instance, if the placebo response were repeatedly found to be within a limited range (e.g., a 15–20% reduction in seizure frequency across clinical trials), the calculated 95% confidence interval would fall within a narrow range and could be therefore used as a historical control. In such a scenario, patients could be randomized to multiple doses of the study drug (since allocation to only one arm could introduce investigator bias) and the efficacy of the study drug could be compared to that of the historical placebo response. In a recent issue of Epilepsy & Behavior, Burneo et al. evaluated the placebo effect in randomized, placebocontrolled, adjunctive clinical trials conducted in patients with medically refractory localization-related epilepsy and included in the Cochrane Database of Systematic Reviews [1]. The placebo effect was assessed with one efficacy variable, namely the 50% responder rate (patients with a 50% or better improvement in seizure frequency compared to baseline). Based on the results, the authors state ‘‘the effects in the placebo arms appear quite homogenous across trials and meta-analyses.’’ The authors based that conclusion on the observation that ‘‘the response to placebo was similar across meta-analyses’’ ranging from 9.3 to 16.6%. This is an Epilepsy & Behavior 4 (2003) 4–5