Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized placebo-controlled trial_Journal of Epilepsy

Authors：

 WUXintong ¹ , SUNHongbin ² , WANGWeimin ³ , LINWeihong ⁴ , YANChuanzhu ⁵ , LIXiaohong ⁶ , LANGSenyang ⁷ , QUHongdang ⁸ , ZHUSuiqiang ⁹ , LUZuneng ¹⁰ , ZHANGKunnan ¹¹ , TAOEnxiang ¹² , LIAOWeiping ¹³ , SUNMeizhen ¹⁴ , GUOCunju ¹⁵ , YANBo ¹ , HAONanya ¹ ,  ZHOUDong ¹

1. Department of Neurology, West China Hospital of Sichuan University, Chengdu 610041, China;
2. Department of Neurology, Sichuan Provincial People's Hospital, Chengdu 614800, China;
3. Epilepsy center, Lanzhou University Second Hospital, Lanzhou 730000, China;
4. Department of Neurology, Jilin University, Changchun 130021, China;
5. Department of Neurology, Qilu Hospital of Shandong University, Ji'nan 250002, China;
6. Department of Neurology, Ji'nan Central Hospital, Ji'nan 250002, China;
7. Department of medical psychology, General Hospital of PLA, Beijing 100853, China;
8. Department of Neurology, The First Affiliated Hospital of Bengbu Medical College Bengbu, Bengbu 233005, China;
9. Department of Neurology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430033, China;
10. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430200, China;
11. Department of Neurology, People's Hospital of Jiangxi Province, Nanchang 330006, China;
12. Department of Neurology, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510120, China;
13. Institute of Neuroscience, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China;
14. Department of Neurology, First Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, China;
15. Department of Neurology, Liaocheng People's Hospital, Liaocheng 252002, China;

Corresponding author：

ZHOUDong, Email: zhoudong66@yahoo.de

Keywords：

Epilepsy; Lacosamide; Add-on therapy; Efficacy; Safety

DOI：

10.7507/2096-0247.20150001

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Objectives To evaluate the efficacy and safety of lacosamide (200mg/d and 400mg/d)when added to 1 to 3 antiepileptic drugs (AEDs) in adults with uncontrolled partial-onset seizures. Methods During this multicenter, double-blind, placebo-controlled trial, patients were randomized to placebo or lacosamide 200 or 400mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments to target dose over 4 weeks and maintained for 12 weeks followed by 12 weeks for withdrawal. The reductions of seizure frequence during maintain period and proportion of ≥50% reduction of seizures frequence were analysed. Besides,adverse effects were also recorded. Results Five hundred fourty patients were randomized, 515 patients completed the trial (Full analysis set, FAS), including 394 were per-protocol set (PPS). The reduction of seizure frequence during maintain period every 4 weeks among 200mg/d,400mg/d group and placebo group were 26.35%,40.12%,21.69%(P=0.000 5) and 25.61%,46.86%,23.06%(P<0.000 1), respectively in FAS and PPS. The proportion of ≥50% reduction of seizures frequence among three groups were 29.82%,38.15%,22.49%(P=0.006 8) and 27.94%,42.37%,22.86%(P=0.002 3), respectively in FAS and PPS. The incidences of adverse events were 5.84%, 36.11%, 19.55% among three groups. Compared with each other, there was statistic significance between 400mg/d and placebo groups. Conclusion In this trial, adjunctive lacosamide significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures. Along with favorable pharmacokinetic and tolerability profiles, these results support further development of lacosamide as an AED.

Citation： WUXintong, SUNHongbin, WANGWeimin, LINWeihong, YANChuanzhu, LIXiaohong, LANGSenyang, QUHongdang, ZHUSuiqiang, LUZuneng, ZHANGKunnan, TAOEnxiang, LIAOWeiping, SUNMeizhen, GUOCunju, YANBo, HAONanya, ZHOUDong. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized placebo-controlled trial. Journal of Epilepsy, 2015, 1(1): 5-16. doi: 10.7507/2096-0247.20150001 Copy

1.	Beydoun A, D'Souza J, Hebert D, et al. Lacosamide:pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Rev Neurother, 2009, 9(1):33-42.
2.	Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia, 2007,48(7):1308-1317.
3.	Halasz P, Kalviainen R, Mazurkiewicz-Beldzinska M, et al. Adjunctive lacosamide for partial-onset seizures:Efficacy and safety results from a randomized controlled trial. Epilepsia, 2009, 50(3):443-453.
4.	Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures:a randomized controlled trial. Epilepsia, 2010, 51(6):958-967.
5.	Sawh SC, Newman JJ, Deshpande S, et al. Lacosamide adjunctive therapy for partial-onset seizures:a meta-analysis. PeerJ, 2013,1:e114.
6.	Grosso S, Parisi P, Spalice A, et al. Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy. Eur J Paediatr Neurol, 2014, 18(1):55-59.
7.	Pasha I, Kamate M, Didagi SK. Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy. Pediatr Neurol, 2014, 51(4):509-514.
8.	Gulati P, Cannell P, Ghia T, et al. Lacosamide as adjunctive therapy in treatment-resistant epilepsy in childhood. J Paediatr Child Health, 2015.
9.	Paquette V, Culley C, Greanya ED, et al. Lacosamide as adjunctive therapy in refractory epilepsy in adults:a systematic review. Seizure, 2015, 25(2):1-17.
10.	de Biase S, Gigli GL, Valente M, et al. Lacosamide for the treatment of epilepsy. Expert Opin Drug Metab Toxicol, 2014, 10(3):459-468.
11.	Santamarina E, Toledo M, Sueiras M, et al. Usefulness of intravenous lacosamide in status epilepticus. J Neurol, 2013, 260(12):3122-3128.
12.	Kellinghaus C, Berning S, Stogbauer F. Intravenous lacosamide or phenytoin for treatment of refractory status epilepticus. Acta Neurol Scand, 2014, 129(5):294-299.
13.	Grosso S, Zamponi N, Bartocci A, et al. Lacosamide in children with refractory status epilepticus. A multicenter Italian experience. Eur J Paediatr Neurol, 2014, 18(5):604-608.
14.	d'Orsi G, Pacillo F, Trivisano M, et al. Lacosamide in absence status epilepticus. Seizure, 2014, 23(5):397-398.
15.	Sutter R, Marsch S, Ruegg S. Safety and efficacy of intravenous lacosamide for adjunctive treatment of refractory status epilepticus:a comparative cohort study. CNS Drugs, 2013, 27(4):321-329.
16.	Legros B, Depondt C, Levy-Nogueira M, et al. Intravenous lacosamide in refractory seizure clusters and status epilepticus:comparison of 200 and 400 mg loading doses. Neurocrit Care, 2014, 20(3):484-488.
17.	Miro J, Toledo M, Santamarina E, et al. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus:a multicentric prospective study. Seizure, 2013, 22(1):77-79.
18.	Novy J, Bartolini E, Bell GS, et al. Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy:a single centre evaluation. Epilepsy Res, 2013, 106(1-2):250-256.
19.	Verrotti A, Loiacono G, Olivieri C, et al. Lacosamide in patients with pharmacoresistant epilepsy. Expert Opin Pharmacother, 2012, 13(14):2065-2072.
20.	Villanueva V, Lopez-Gomariz E, Lopez-Trigo J, et al. Rational polytherapy with lacosamide in clinical practice:results of a Spanish cohort analysis RELACOVA. Epilepsy Behav, 2012, 23(3):298-304.
21.	Husain A, Chung S, Faught E, et al. Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide:results from a Phase Ⅲ open-label extension trial. Epilepsia, 2012, 53(3):521-528.
22.	Stephen LJ, Kelly K, Parker P, et al. Adjunctive lacosamide in clinical practice:sodium blockade with a difference? Epilepsy Behav, 2011, 22(3):499-504.
23.	Flores L, Kemp S, Colbeck K, et al. Clinical experience with oral lacosamide as adjunctive therapy in adult patients with uncontrolled epilepsy:a multicentre study in epilepsy clinics in the United Kingdom (UK). Seizure, 2012, 21(7):512-517.
24.	Harden CL, Cohn A, Lowe M, et al. Initial post marketing experience with lacosamide in adult patients with epilepsy. Epilepsy Res, 2012, 98(2-3):260-263.
25.	Kamel JT, DeGruyter MA, D'Souza WJ, et al. Clinical experience with using lacosamide for the treatment of epilepsy in a tertiary centre. Acta Neurol Scand, 2013, 127(3):149-153.
26.	Villanueva V, Lopez FJ, Serratosa JM, et al. Control of seizures in different stages of partial epilepsy:LACO-EXP, a Spanish retrospective study of lacosamide. Epilepsy Behav, 2013, 29(2):349-356.
27.	Wehner T, Bauer S, Hamer HM, et al. Six months of postmarketing experience with adjunctive lacosamide in patients with pharmacoresistant focal epilepsy at a tertiary epilepsy center in Germany. Epilepsy Behav, 2009, 16(3):423-425.
28.	Garcia-Morales I, Delgado R T, Falip M, et al. Early clinical experience with lacosamide as adjunctive therapy in patients with refractory focal epilepsy and nocturnal seizures. Seizure, 2011, 20(10):801-804.
29.	Verrotti A, Loiacono G, Pizzolorusso A, et al. Lacosamide in pediatric and adult patients:comparison of efficacy and safety. Seizure, 2013, 22(3):210-216.
30.	Wechsler RT, Li G, French J, et al. Conversion to lacosamide monotherapy in the treatment of focal epilepsy:results from a historical-controlled, multicenter, double-blind study. Epilepsia, 2014, 55(7):1088-1098.
31.	Wasterlain CG, Stohr T, Matagne A. The acute and chronic effects of the novel anticonvulsant lacosamide in an experimental model of status epilepticus. Epilepsy Res, 2011, 94(1-2):10-17.
32.	Albers JM, Moddel G, Dittrich R, et al. Intravenous lacosamide——an effective add-on treatment of refractory status epilepticus. Seizure, 2011, 20(5):428-430.
33.	Goodwin H, Hinson HE, Shermock KM, et al. The use of lacosamide in refractory status epilepticus. Neurocrit Care, 2011, 14(3):348-353.
34.	Hofler J, Unterberger I, Dobesberger J, et al. Intravenous lacosamide in status epilepticus and seizure clusters. Epilepsia, 2011, 52(10):e148-152.
35.	Kellinghaus C, Berning S, Immisch I, et al. Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand, 2011, 123(2):137-141.
36.	Cherry S, Judd L, Muniz JC, et al. Safety and efficacy of lacosamide in the intensive care unit. Neurocrit Care, 2012, 16(2):294-298.
37.	Mnatsakanyan L, Chung JM, Tsimerinov EI, et al. Intravenous Lacosamide in refractory nonconvulsive status epilepticus. Seizure, 2012, 21(3):198-201.
38.	Garces M, Villanueva V, Mauri JA, et al. Factors influencing response to intravenous lacosamide in emergency situations:LACO-IV study. Epilepsy Behav, 2014, 36(6):144-152.
39.	Chinnasami S, Rathore C, Duncan JS. Sinus node dysfunction:an adverse effect of lacosamide. Epilepsia, 2013, 54(6):e90-93.
40.	DeGiorgio AC, Desso E, Lee L, et al. Ventricular tachycardia associated with lacosamide co-medication in drug-resistant epilepsy. Epilepsy Behav Case Rep, 2012, 1(1):26-28.
41.	Kaufman KR, Velez AE, Wong S, et al. Low-dose lacosamide-induced atrial fibrillation:Case analysis with literature review. Epilepsy Behav Case Rep, 2013, 1(1):22-25.

1. Beydoun A, D'Souza J, Hebert D, et al. Lacosamide:pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Rev Neurother, 2009, 9(1):33-42.
2. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia, 2007,48(7):1308-1317.
3. Halasz P, Kalviainen R, Mazurkiewicz-Beldzinska M, et al. Adjunctive lacosamide for partial-onset seizures:Efficacy and safety results from a randomized controlled trial. Epilepsia, 2009, 50(3):443-453.
4. Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures:a randomized controlled trial. Epilepsia, 2010, 51(6):958-967.
5. Sawh SC, Newman JJ, Deshpande S, et al. Lacosamide adjunctive therapy for partial-onset seizures:a meta-analysis. PeerJ, 2013,1:e114.
6. Grosso S, Parisi P, Spalice A, et al. Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy. Eur J Paediatr Neurol, 2014, 18(1):55-59.
7. Pasha I, Kamate M, Didagi SK. Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy. Pediatr Neurol, 2014, 51(4):509-514.
8. Gulati P, Cannell P, Ghia T, et al. Lacosamide as adjunctive therapy in treatment-resistant epilepsy in childhood. J Paediatr Child Health, 2015.
9. Paquette V, Culley C, Greanya ED, et al. Lacosamide as adjunctive therapy in refractory epilepsy in adults:a systematic review. Seizure, 2015, 25(2):1-17.
10. de Biase S, Gigli GL, Valente M, et al. Lacosamide for the treatment of epilepsy. Expert Opin Drug Metab Toxicol, 2014, 10(3):459-468.
11. Santamarina E, Toledo M, Sueiras M, et al. Usefulness of intravenous lacosamide in status epilepticus. J Neurol, 2013, 260(12):3122-3128.
12. Kellinghaus C, Berning S, Stogbauer F. Intravenous lacosamide or phenytoin for treatment of refractory status epilepticus. Acta Neurol Scand, 2014, 129(5):294-299.
13. Grosso S, Zamponi N, Bartocci A, et al. Lacosamide in children with refractory status epilepticus. A multicenter Italian experience. Eur J Paediatr Neurol, 2014, 18(5):604-608.
14. d'Orsi G, Pacillo F, Trivisano M, et al. Lacosamide in absence status epilepticus. Seizure, 2014, 23(5):397-398.
15. Sutter R, Marsch S, Ruegg S. Safety and efficacy of intravenous lacosamide for adjunctive treatment of refractory status epilepticus:a comparative cohort study. CNS Drugs, 2013, 27(4):321-329.
16. Legros B, Depondt C, Levy-Nogueira M, et al. Intravenous lacosamide in refractory seizure clusters and status epilepticus:comparison of 200 and 400 mg loading doses. Neurocrit Care, 2014, 20(3):484-488.
17. Miro J, Toledo M, Santamarina E, et al. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus:a multicentric prospective study. Seizure, 2013, 22(1):77-79.
18. Novy J, Bartolini E, Bell GS, et al. Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy:a single centre evaluation. Epilepsy Res, 2013, 106(1-2):250-256.
19. Verrotti A, Loiacono G, Olivieri C, et al. Lacosamide in patients with pharmacoresistant epilepsy. Expert Opin Pharmacother, 2012, 13(14):2065-2072.
20. Villanueva V, Lopez-Gomariz E, Lopez-Trigo J, et al. Rational polytherapy with lacosamide in clinical practice:results of a Spanish cohort analysis RELACOVA. Epilepsy Behav, 2012, 23(3):298-304.
21. Husain A, Chung S, Faught E, et al. Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide:results from a Phase Ⅲ open-label extension trial. Epilepsia, 2012, 53(3):521-528.
22. Stephen LJ, Kelly K, Parker P, et al. Adjunctive lacosamide in clinical practice:sodium blockade with a difference? Epilepsy Behav, 2011, 22(3):499-504.
23. Flores L, Kemp S, Colbeck K, et al. Clinical experience with oral lacosamide as adjunctive therapy in adult patients with uncontrolled epilepsy:a multicentre study in epilepsy clinics in the United Kingdom (UK). Seizure, 2012, 21(7):512-517.
24. Harden CL, Cohn A, Lowe M, et al. Initial post marketing experience with lacosamide in adult patients with epilepsy. Epilepsy Res, 2012, 98(2-3):260-263.
25. Kamel JT, DeGruyter MA, D'Souza WJ, et al. Clinical experience with using lacosamide for the treatment of epilepsy in a tertiary centre. Acta Neurol Scand, 2013, 127(3):149-153.
26. Villanueva V, Lopez FJ, Serratosa JM, et al. Control of seizures in different stages of partial epilepsy:LACO-EXP, a Spanish retrospective study of lacosamide. Epilepsy Behav, 2013, 29(2):349-356.
27. Wehner T, Bauer S, Hamer HM, et al. Six months of postmarketing experience with adjunctive lacosamide in patients with pharmacoresistant focal epilepsy at a tertiary epilepsy center in Germany. Epilepsy Behav, 2009, 16(3):423-425.
28. Garcia-Morales I, Delgado R T, Falip M, et al. Early clinical experience with lacosamide as adjunctive therapy in patients with refractory focal epilepsy and nocturnal seizures. Seizure, 2011, 20(10):801-804.
29. Verrotti A, Loiacono G, Pizzolorusso A, et al. Lacosamide in pediatric and adult patients:comparison of efficacy and safety. Seizure, 2013, 22(3):210-216.
30. Wechsler RT, Li G, French J, et al. Conversion to lacosamide monotherapy in the treatment of focal epilepsy:results from a historical-controlled, multicenter, double-blind study. Epilepsia, 2014, 55(7):1088-1098.
31. Wasterlain CG, Stohr T, Matagne A. The acute and chronic effects of the novel anticonvulsant lacosamide in an experimental model of status epilepticus. Epilepsy Res, 2011, 94(1-2):10-17.
32. Albers JM, Moddel G, Dittrich R, et al. Intravenous lacosamide——an effective add-on treatment of refractory status epilepticus. Seizure, 2011, 20(5):428-430.
33. Goodwin H, Hinson HE, Shermock KM, et al. The use of lacosamide in refractory status epilepticus. Neurocrit Care, 2011, 14(3):348-353.
34. Hofler J, Unterberger I, Dobesberger J, et al. Intravenous lacosamide in status epilepticus and seizure clusters. Epilepsia, 2011, 52(10):e148-152.
35. Kellinghaus C, Berning S, Immisch I, et al. Intravenous lacosamide for treatment of status epilepticus. Acta Neurol Scand, 2011, 123(2):137-141.
36. Cherry S, Judd L, Muniz JC, et al. Safety and efficacy of lacosamide in the intensive care unit. Neurocrit Care, 2012, 16(2):294-298.
37. Mnatsakanyan L, Chung JM, Tsimerinov EI, et al. Intravenous Lacosamide in refractory nonconvulsive status epilepticus. Seizure, 2012, 21(3):198-201.
38. Garces M, Villanueva V, Mauri JA, et al. Factors influencing response to intravenous lacosamide in emergency situations:LACO-IV study. Epilepsy Behav, 2014, 36(6):144-152.
39. Chinnasami S, Rathore C, Duncan JS. Sinus node dysfunction:an adverse effect of lacosamide. Epilepsia, 2013, 54(6):e90-93.
40. DeGiorgio AC, Desso E, Lee L, et al. Ventricular tachycardia associated with lacosamide co-medication in drug-resistant epilepsy. Epilepsy Behav Case Rep, 2012, 1(1):26-28.
41. Kaufman KR, Velez AE, Wong S, et al. Low-dose lacosamide-induced atrial fibrillation:Case analysis with literature review. Epilepsy Behav Case Rep, 2013, 1(1):22-25.

Journal of Epilepsy

Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized placebo-controlled trial

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