Abstracts

Rationale: The efficacy of new antiepileptic drugs (AEDs) in patients suffering from drug-resistant partial epilepsy is usually investigated using placebo-controlled randomized controlled trials (RCTs). Since head-to-head trials are usually lacking in this population, only indirect comparisons can be performed to test potential difference in the efficacy of new AEDs. However, indirect comparisons raise several methodological issues which have not been systematically investigated. In particular, the last observation carried forward (LOCF) method used to report the primary efficacy endpoints in all add-on RCTs might have an important impact on the calculation of the 50% responder rate. Specifically, this method might lead to an overestimation of the responder rate in RCTs associated with a high withdrawal rate Methods: Two electronic databases were searched for RCTs investigating AEDs in the add-on treatment of drug-resistant partial epilepsy in adults. The 50% responder rate was calculated in two different ways: 1) according to the standard LOFC method available in all relevant publications; 2) in the subgroup of patients who completed the double-blind phase (Completers). This latter information was usually not provided in the publications, leading us to contact all pharmaceutical companies involved in the development of the investigated AEDs to obtain these data. The 50% responder rate was calculated using the two above values (LOFC and completers), and the ITT population as denominator. For each trial, we calculated the relative risk (RR) of the 50% responder rate between active AEDs treatment and placebo groups. We then compared the LOFC and completers RR, across trials and AEDs. We also searched for correlation between the withdrawal rate and the difference observed between the LOFC and completers 50% responder rates Results: We found a total of 55 RCTs and 14 AEDs. However, information regarding the 50% responder rate in completers was provided by only three of the contacted companies for four AEDs, i.e. Gabapentin (GBP), Levetircetam (LEV), Pregabalin (PGB) and Topiramate (TPM). Overall, relevant data were available for 17 RCTs, including four GBP, three LEV, four PGB and six TPM. The mean 50% responder rate in patients receiving AEDs was significantly higher in LOFC than in completers (p=0.001) whereas no significant difference was observed in the response to placebo. There was a nonsignificant trend toward higher RR of the 50% responder rate in LOFC than in completers (p=0.096). There was a very significant positive correlation between the withdrawal rate and the difference observed between the LOFC and completers 50% responder rates (r=0.88, p<0.001) Conclusions: The standard LOFC method used in add-on RCTs performed in patients with drug resistant partial epilepsy lead to an overestimatation of the 50% responder rate that positively correlates with the withdrawal rate. Efficacy data in completers should be systematically reported and incorporated in the evaluation of each new compounds as well as in the indirect comparisons between AEDs