OBJECTIVES: To compare trials of the four anti-epileptic drugs (AEDs) approved specifically for the adjunctive treatment of primary generalized tonic-clonic seizures (PGTCS):  topiramate [TPM] (1999), lamotrigine [LTG] (2006), levetiracetam [LEV] (2007), lamotrigine-XR [LTG-XR] (2010), and perampanel [PER] (2015). METHODS: Trial data were identified through a systematic literature review.  Main inclusion criteria: randomized, controlled, PGTCS with or without other generalized seizure types, and published 1989-2014.  Key exclusion criteria: predominantly children/adolescents and intravenous drug study.  Data were abstracted from indexed publications, clinicaltrials.gov, and regulatory reports of the United States Food and Drug Administration and European Medicines Agency. RESULTS: Five PGTCS trials [TPM-RCT (n=80), LTG-RCT (n=117), LEV-RCT (n=164), LTG-XR-RCT (n=146), PER-RCT (n=163)] were identified.  All trials were placebo-controlled where baseline AEDs were continued into the trial and consisted of the standard of care (SOC) at the time.   Trial designs were similar with minor exceptions: PER-RCT allowed 1-3 baseline AEDs (others 1-2), LEV-RCT and PER-RCT had shorter titration periods (4 versus 7 & 8 weeks), and LEV-RCT had the longest maintenance period (20 versus 12 & 13 weeks).  Baseline PGTCS frequency was similar between trials except TPM-RCT which was higher (4.5-5.0 versus 2.3-3.0 per 28 days).  The presence of LTG, LEV, and zonisamide in the SOC increased over time while the use of carbamazepine, phenytoin, and phenobarbital decreased.  Valproate and TPM use fluctuated but appeared stable.  In the latest phase III trial, PER-RCT had the following SOC composition, 43% valproate, 39% LTG, 15% TPM, 31% LEV, 12% zonisamide, 8% carbamazepine, 6% phenytoin, and 4% phenobarbital. CONCLUSIONS: Our review indicates that while the trial designs have remained similar over time, the SOC has evolved with the approval of new PGTCS medications.  The latest trial, PER-RCT, has an SOC that is comprised heavily of the most recently approved PGTCS drugs.