Objective To evaluate efficacy and safety of lacosamide (up to 12 mg/kg/day or 400 mg/day) as adjunctive treatment for uncontrolled primary generalised tonic-clonic seizures (PGTCS) in patients (≥4 years) with idiopathic generalised epilepsy (IGE).
Methods Phase 3, double-blind, randomised, placebo-controlled trial (SP0982; NCT02408523) in patients with IGE and PGTCS taking 1–3 concomitant antiepileptic drugs. Primary outcome was time to second PGTCS during 24-week treatment.
Results 242 patients were randomised and received ≥1 dose of trial medication (lacosamide/placebo: n=121/n=121). Patients (mean age: 27.7 years; 58.7% female) had a history of generalised-onset seizures (tonic-clonic 99.6%; myoclonic 38.8%; absence 37.2%). Median treatment duration with lacosamide/placebo was 143/65 days. Risk of developing a second PGTCS during 24-week treatment was significantly lower with lacosamide than placebo (Kaplan-Meier survival estimates 55.27%/33.37%; HR 0.540, 95% CI 0.377 to 0.774; p<0.001; n=118/n=121). Median time to second PGTCS could not be estimated for lacosamide (>50% of patients did not experience a second PGTCS) and was 77.0 days for placebo. Kaplan-Meier estimated freedom from PGTCS at end of the 24-week treatment period (day 166) for lacosamide/placebo was 31.3%/17.2% (difference 14.1%; p=0.011). More patients on lacosamide than placebo had ≥50% (68.1%/46.3%) or ≥75% (57.1%/36.4%) reduction from baseline in PGTCS frequency/28 days, or observed freedom from PGTCS during treatment (27.5%/13.2%) (n=119/n=121). 96/121 (79.3%) patients on lacosamide had treatment-emergent adverse events (placebo 79/121 (65.3%)), most commonly dizziness (23.1%), somnolence (16.5%), headache (14.0%). No patients died during the trial.
Conclusions Lacosamide was efficacious and generally safe as adjunctive treatment for uncontrolled PGTCS in patients with IGE.
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Contributors DGV contributed to the conception and design of the trial, and was the coordinating investigator. DGV, SK, TJO and MW participated in acquisition of data as trial investigators. RR was the trial physician. MB was the clinical programme director. PW was the trial statistician. All authors participated in analysis and interpretation of results and critical revision of the article for intellectual content. All authors approved the final version of the manuscript for publication.
Funding This trial was sponsored by UCB Pharma.
Competing interests DGV received speaker honoraria from Eisai, Greenwich Biosciences, Lundbeck, Sunovion and UCB Pharma; his institution received payments for his services as a principal investigator on randomised controlled trials sponsored by Biogen, Eisai, SK Life Science and UCB Pharma; he served as an advisor to Otsuka Pharmaceutical Development and Commercialisation and SK Life Science. SK received speaker honoraria from Desitin, Eisai and UCB Pharma. TJO received research funding from Anavex, Biogen, Eisai, Praxis Precision Medicines, UCB Pharma and Zynerba. MW received speaker honoraria from Eisai, Otsuka Pharmaceutical and UCB Pharma. MB, BS-B, PW and RR are employees of UCB Pharma.
Patient consent for publication Not required.
Ethics approval The trial was conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and local laws. The trial protocol, amendments and patient-informed consent were reviewed by a national, regional or independent ethics committee or institutional review board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Underlying data from this manuscript may be requested by qualified researchers 6 months after product or indication approval in the USA and/or Europe, or global development is discontinued, and 18 months after trial completion. Investigators may request access to anonymised individual patient-level data and redacted trial documents, which may include: analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications and clinical study report. Prior to use of the data, proposals need to be approved by an independent review panel at www.vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password-protected portal.
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