Abstracts

Rationale: The effectiveness of many antiepileptic drugs (AEDs) in treating nonconvulsive seizures (NCS) in critically ill patients has not been studied in prospective, randomized trials. In this study we compared the utility of lacosamide (LCM) with fosphenytoin (fPHT) in this patient population in the Treatment of Recurrent Electrographic Nonconvulsive Seizures (TRENdS) trial.Methods: This was a prospective, multicenter, randomized, active-controlled, noninferiority, open-label trial with blinded electroencephalogram (EEG) review. Patients diagnosed with NCS by continuous EEG (cEEG) monitoring were enrolled. Treatment was randomized to IV LCM 400 mg bolus followed by LCM 200 mg every 12 hours or IV fPHT 20 mg PE/kg bolus followed by 2.5 mg PE/kg every 12 hours. A rebolus of LCM 200 mg or fPHT 5 mg PE/kg was administered if a breakthrough electrographic seizure occurred within 2-8 hours after bolus dose. The primary end point was no recurrence of electrographic seizures (with or without clinical correlate) for 24 hours following bolus (or rebolus, if administered) of study drug as determined by blinded EEG reviewers. The response rate (no further seizures) of the LCM arm was compared to the fPHT arm and the 90% confidence interval (CI) was determined. A modified intent to treat (mITT; those patients with at least 67% of cEEG monitoring completed) population was used for efficacy analysis. Noninferiority of LCM to fPHT was concluded if the lower bound of the CI for relative risk was above 0.8.Results: The ITT population included 74 subjects (37 in both LCM and fPHT arms), whereas the mITT population included 62 subjects (30 in the LCM arm, 32 in the fPHT arm). The safety population (those that received at least one dose of study drug) included 72 subjects (35 in the LCM group, 37 in the fPHT group). The mean age (ITT population) was 63.6 years; 38 were women. The response rate (mITT population) was 19/30 (63.3%) for the LCM group and 16/32 (50.0%) for the fPHT group. The risk ratio was 1.27 (90% CI = 0.875, 1.833) and the p-value for establishing noninferiority for LCM was 0.021 Treatment emergent adverse events (AE) within 24 hours of study drug administration were noted in 9/35 (25.7%) of LCM and 9/37 (24.3%) of fPHT patients. Serious AE occurred in 5/35 (14.3%) of LCM and 4/37 (10.8%) of fPHT patients. Treatment was discontinued in 2 (5.7%) and 3 (8.1%) patients in the LCM and fPHT arms. The rates of specific AE for LCM and fPHT arms were as follows: arrhythmias (5.7% vs 8.1%), acute respiratory failure (2.9% vs 0) and hypotension (5.7% vs 5.4%).Conclusions: LCM was noninferior compared to fPHT in controlling nonconvulsive seizures noted on cEEG. TEAE were comparable with both AEDs. LCM can be considered an alternative to fPHT in the treatment of NCS detected on cEEG monitoring in critically ill patients. Acknowledgement: This was an Investigator Initiated Study funded by UCB Pharma.