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 4"5 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et al 8, in the development of Felbamate, is the performance of monotherapy trials in patients whose AEDs had been withdrawn to facilitate capture of seizures by telemetry, as part of a preoperative assessment protocol.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