Accounting for repeat enrollments during an emergency clinical trial: the Rapid Anticonvulsant Medications Prior to Arrival Trial (RAMPART).

In most clinical trials, patients participate once. In trials of emergency conditions such as status epilepticus with early enrollment, patients may inadvertently or intentionally be enrolled multiple times. Many important, high-morbidity emergency conditions recur in at-risk individuals. Specific examples include status asthmaticus, head trauma, and status epilepticus.1 In the prehospital setting or early in the emergency department (ED) visit, evaluations of treatments for such conditions by clinical trials frequently employ exception from informed consent (EFIC), which makes it more difficult to prospectively identify potential reenrollers.2 Within a clinical trial, repeated measurements of outcome data from the same individual may be positively correlated. Ignoring this correlation may bias the variance estimate and lead to spurious results.3 Independence of observations is a key assumption of many statistical techniques.4 In brief, independence means that knowledge of a given observation does not affect the probability distribution of other observations. In a typical clinical trial, by measuring an outcome in one patient, the outcome probability distribution of the other is unaffected. However, independence is commonly violated with clustered data. In the case of an EFIC trial with repeat enrollments, if some patients are more or less likely to respond to treatment, then additional enrollments by those patients may not provide truly independent information. In this case, the extent to which some patients have either highly refractory or easily treated status epilepticus can lead to misestimation of the confidence intervals of the treatment effect of interest. The planning of clinical trials requires careful consideration regarding the preexisting state of knowledge within the disease, along with the scientific and logistical priorities of the actual experiment to be conducted. The field of emergency care research is unique for many reasons; of particular interest within this setting is the potential recurrent nature of serious conditions. As such, one way of addressing the correlation within subjects who may present with the disease in question multiple times is to only enroll a patient once in a clinical trial. On the other hand, practical concerns may make it challenging to determine that a patient has been enrolled previously when an intervention is being delivered under EFIC. A common approach is to limit to the first occurrence of the disease within individual, as this will eliminate the possibility of within-subject correlation biasing the results. Under an EFIC trial, however, the patient may have repeated exposure to a research intervention without the prospect of contributing to scientific knowledge on the primary efficacy outcome. Such repeated enrollments may contribute information regarding safety, however. As such, when planning emergency care research it is important to consider the scientific, ethical, and logistical effects of the approach that will be used to account for repeated presentations with the same condition. Our objectives were to describe the frequency of repeat enrollment within a specific EFIC trial of benzodiazepine treatment for prehospital status epilepticus and the effect of repeat enrollments on the analysis of the primary outcome.