Advancing the treatment in primary generalized tonic-clonic seizures: A novel time-to-event study of lacosamide

06 Sep 2021

Professor Philippe Ryvlin  

Chair of the Department of Clinical Neurosciences,  
Lausanne University Hospital,  


Professor Hideaki Shiraishi  

Department of Pediatrics,
Hokkaido University Hospital
Vice Director,
Hokkaido University Hospital Epilepsy Center


Professor Terence O’Brien

Department of Neuroscience,  
Central Clinical School,  
Alfred Health and Monash University,  


Professor Jacqueline A. French  

Department of Neurology,  
Comprehensive Epilepsy Center,  
New York University Langone School of Medicine,  
United States   

Primary generalized tonic-clonic seizure (PGTCS) is the most serious seizure type in idiopathic generalized epilepsy (IGE) and a known risk of sudden unexpected death in epilepsy (SUDEP).1 Co-occurring with typical absences and myoclonic seizures, PGTCS is experienced by 74% of IGE patients.2,3 Despite its high prevalence, PGTCS and its treatment have been the subject of relatively few robust clinical studies.4 In the recent virtual 13th Asian and Oceanian Epilepsy Congress, Professor Philippe Ryvlin from the Lausanne University Hospital in Switzerland, Professor Hideaki Shiraishi from the Hokkaido University Hospital Epilepsy Center in Japan, Professor Terence O’Brien from the Alfred Health and Monash University in Australia, and Professor Jacqueline A. French from the New York University Langone School of Medicine in the United States shared their insights on the latest clinical trial involving one of the treatments, lacosamide*, for patients with PGTCS.

Unmet need for patients living with IGE and PGTCS

Regardless of origin, uncontrolled PGTCS is associated with a serious burden for patients similar to frequent seizures. Uncontrolled PGTCS is also associated with a loss of grey matter in the brain, negative impact on cognition, impaired social functioning, and reduced quality of life.5-8 However, very little research is published on PGTCS associated with IGE despite its severity.3,4,9 As a result, a gap exists in the evidence of available treatment options for drug-resistant patients, and most current options are based on small-scale studies (Table 1).1 As clinical decisions should be made based on rigorous evidence from well-controlled clinical trials, more randomized, blinded and prospective controlled trials are required to recommend the optimal antiepileptic drugs (AEDs) for this patient group.1

Lacosamide as an effective and safe option for PGTCS in the VALOR study

Although sodium channel blockers have been the mainstay of the management of focal and generalized tonic-clonic seizures (GTCS) for more than 70 years, there is concern on the suitability of this treatment for PGTCS as sodium channel blockers may aggravate seizures in IGE.10,11 However, due to the frequent overestimation of seizure aggravation by clinicians and patients, as well as the low quality of evidence for seizure aggravation caused by sodium channel blockers, the negative impact of this class of drugs on seizures is still debatable.12,13 In fact, recent studies on sodium channel blockers, such as lamotrigine and lacosamide, supported their efficacy in treating PGTCS.14,15

To evaluate the efficacy of oral adjunctive lacosamide versus placebo for uncontrolled PGTCS, the VALOR study recruited patients who were at least 4 years old with IGE and currently taking 1 to 3 concomitant AEDs’ independent of the number of prior failed AEDs.15 In this double-blinded, placebo-controlled, multicenter, time-to-event study, 242 patients with history of generalized-onset seizures (99.6% experienced tonic-clonic seizures; 38.8% with myoclonic; 37.2% with absence) were randomized and received at least one dose of trial medication (n=121 for lacosamide; n=121 for placebo).15

From the study results, patients on adjunctive lacosamide had a 46% lower risk of developing a second PGTCS during the 24-week treatment period compared with placebo (HR=0.540; 95% CI: 0.377-0.774; p<0.001; Figure 1).15 A numerically lower risk of developing second PGTCS during the treatment period was also observed regardless of age or the number of concomitant or lifetime AEDs.15 Notably, a significantly higher estimated PGTCS freedom rate was observed with adjunctive lacosamide compared with placebo (31.3% with lacosamide vs. 17.2% with placebo; p=0.011).15

Adjunctive lacosamide was generally well-tolerated.15 Dizziness, somnolence and headache were the only treatment-emergent adverse events (TEAEs) reported by 10% or more patients, consistent with those reported previously in patients with focal seizures and in the open-label pilot study among patients with IGE and uncontrolled PGTCS.15 From clinical experience, Prof. O'Brien noted that effects on mood, behavior and cognition were not common with lacosamide. Furthermore, while one patient (2.1%) on lacosamide and one patient (2.0%) on placebo had new occurrence of myoclonic seizures, no patients on lacosamide or placebo had new occurrence of absence seizures.15 Three (2.5%) patients on lacosamide had a TEAE of myoclonic epilepsy and one (0.8%) patient on placebo had a TEAE of myoclonus; none of these TEAEs were serious.15 Overall, the results of this trial supported the use of adjunctive oral lacosamide for the treatment of uncontrolled PGTCS in patients at least 4-years-old with IGE.15

Implications of the VALOR results

When reviewing the results of the VALOR study, Prof. French considered that a major added value of the results arises from the uniqueness of its study design. The time-to-event design of the VALOR trial was based on the post hoc analyses of a study for lamotrigine in PGTCS that confirmed the potential utility of “time to Nth seizure” as an endpoint for seizure studies.15 “Lamotrigine had significantly longer time to third seizure versus placebo. As lacosamide reaches the effective dose earlier, time to second seizure was chosen as a primary endpoint for the VALOR study,” Prof. French explained.

Compared with the traditional clinical trials in IGE and PGTCS, which harm the participants with lengthy exposure to placebo or ineffective treatments, the novel time-to-event design is more patient-centric as analyzing the time to second seizure further reduces the trial duration by limiting the treatment period for non-responders, ultimately reducing the exposure to ineffective treatment.15 As such, the study design considered the needs of patients by improving the inclusion criteria and the prospective baseline period of the study population. With a smaller number of seizures (at least 3) required for patients to participate in VALOR compared with previous trials, the study population could be more comparable to the real-life condition.15 Similarly, the duration for prospective baseline period was shortened (4 weeks) compared with traditional design (8 weeks), such that patients can move on from ineffective medication over a shorter period of time.15 “Patients can exit the study quickly and continue to seek effective therapy,” Prof. French described.

Other than the time-to-event design, the inclusion of patients as young as 4 years old in the VALOR study supported the use of lacosamide or other sodium channel blockers in a broad range of patients.15 When evaluating the prerequisites of choosing sodium channel blockers over other types of AEDs to treat PGTCS, Prof. Shiraishi stated that sodium channel blockers should be considered for infants and adolescents as the drug class is generally safe in these populations.

When asked about the position of the VALOR results among randomized controlled trials focusing on other traditional sodium channel blockers, Prof. O’Brien pointed out that as VALOR enrolled patients with uncontrolled PGTCS who experienced at least one prior AED, the trial does not provide supporting evidence for the untreated population.15 That said, VALOR indicated the better tolerability of lacosamide than other AEDs. When considering lacosamide as a treatment for PGTCS, Prof. O’Brien concluded that, “Lacosamide has a nice role in patients with IGE, positioned as a second-line therapy for PGTCS.”


The benefits of adjunctive lacosamide over placebo were demonstrated in the VALOR trial with a significantly higher PGTCS freedom rate, lower risk of a second PGTCS and a generally well-tolerated safety profile which was consistent with its previous studies in focal epilepsy. It is hoped that with the novel time-to-event study design that takes the needs of patients into consideration, the results of this trial could support the use of adjunctive oral lacosamide for the treatment of uncontrolled PGTCS in patients ≥4 years of age with IGE.


*In Hong Kong, lacosamide is indicated as monotherapy and adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in adults, adolescents, and children from 4 years of age with epilepsy. lacosamide is not indicated for treatment of primary generalized tonic-clonic seizure in Hong Kong. This advertorial may contain off-label information. The use of lacosamide in any way other than that specified by the Summary of Product Characteristics is off-label and cannot be recommended by UCB Pharma (Hong Kong) Limited. Please consult your local product information.

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