Monotherapy trials: endpoints

Monotherapy antiepileptic drug (AED) trials can optimally provide information concerning efficacy and tolerability of one drug compared with placebo, as well as to different doses or rates of administration. Commonly, a drug is compared with one or more other drugs. The outcome measures will be dictated by the questions being asked. In most comparative studies, the single overall result that best defines success or failure is time of continuation on drug as expressed in a life table. Discontinuation before planned completion of the study implies insufficient efficacy or unacceptable adverse effects. A statistically significant difference between treatments provides important support for recommending the drug or dose with the best outcome. The criteria for continuation/discontinuation are defined in the design based on the expected outcome. The outcome of primary importance is efficacy in prevention of seizures or a decrease in severity. Complete control for the duration of the study is the ultimate goal but in some populations may not be possible. The number of subjects entering remission gives further information about long term outcome. Time to first (nth) seizure provides similar evidence of efficacy. Seizure rates allow comparisons of subjects retained for different lengths of time in the trial. Differences in seizure severity may be of clinical importance and multiple efforts have been made to develop instruments to accurately measure this outcome. Adverse effects of the drugs are the second major outcome. These can be expressed as incidence and/or prevalence. The presence and frequency of side effects will depend on how the study is designed and whether these effects are specifically sought by the investigators. Serious systemic safety outcomes are monitored, but the relative infrequency of occurrence and number of subjects in the trials usually do not provide enough power to detect statistically significant differences except for rash. Tolerability is more easily documented but is difficult to access accurately in the absence of placebo controls. Frequency, severity and persistence are measurable. Specific unwanted types of drug effects can be specifically studied using detailed neuropsychological test batteries. Some information concerning pharmacokinetic properties may be obtained but are better assessed in other types of trials. A final important outcome is the effect of drug therapy on quality of life. Although a favorable finding in this outcome is most desirable, the measures used are much less precise than those for efficacy and adverse effects.