CNS Drugs

, Volume 24, Issue 12, pp 1041–1054

Examining the Clinical Utility of Lacosamide

Pooled Analyses of Three Phase II/III Clinical Trials
  • Steve Chung
  • Elinor Ben-Menachem
  • Michael R. Sperling
  • William Rosenfeld
  • Nathan B. Fountain
  • Selim Benbadis
  • David Hebert
  • Jouko Isojärvi
  • Pamela Doty
Original Research Article

Abstract

Background: Lacosamide is an antiepileptic drug (AED) approved for the adjunctive treatment of partial-onset seizures in adults. Completed phase II/III clinical trials of lacosamide provide a valuable opportunity to evaluate clinically relevant aspects of the resulting large patient pool.

Objective: To provide insight into the clinical utility of lacosamide by performing a priori-defined and post hoc analyses on a large, pooled patient population.

Study Design: Pooled data from three randomized, double-blind, multicentre, placebo-controlled phase II/III trials.

Patients: Adult patients with partial-onset seizures with or without secondary generalization (N = 1294).

Intervention: Four- to six-week titration followed by 12-week maintenance treatment with lacosamide (Vimpat®) 200, 400 or 600mg/day or placebo.

Main Outcome Measure:A priori- defined primary efficacy variables for the pooled analysis were change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase; a priori-defined secondary efficacy variables were the proportion of patients achieving a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate), the proportion of Maintenance Phase completers remaining seizure free throughout the entire Maintenance Phase and the percentage of seizure-free days during the Maintenance Phase for patients entering the Maintenance Phase. The pooled analyses of the change in seizure frequency, and 50% and 75% responder rates were performed with an intent-to-treat (ITT) approach, including all patients receiving at least one dose of trial medication and having at least one post-baseline efficacy assessment. Similar analyses of the two primary efficacy variables and 75% responder rates were also performed using a modified ITT population (ITTm) that included ITT patients who entered the Maintenance Phase. Additional post hoc efficacy analyses were an evaluation of onset of efficacy and assessment of efficacy in patients grouped by prior surgical history and individual concomitant AED use. In addition, pharmacokinetic-pharmacodynamic modelling was performed, and safety data were assessed.

Results: In this pooled analysis of 1294 difficult-to-treat patients, all three dosages of lacosamide (200, 400 and 600 mg/day) showed a significant improvement compared with placebo for median percent seizure reduction (ITT and ITTm; p < 0.05 for 200 mg/day, p < 0.001 for 400 and 600 mg/day), as well as for 50% responder rate (ITT and ITTm; p <0.05 for 200 mg/day, p<0.001 for 400 and 600 mg/day). Evaluation of 75% responder rate in the phase II/III pooled population showed that a significantly higher proportion of patients randomized to lacosamide 400 or 600 mg/day achieved a ≥75% reduction in seizure frequency compared with placebo (ITT and ITTm; p < 0.001); statistical significance was not observed for lacosamide 200 mg/day (ITT and ITTm). A total of 2.7%, 3.3% and 4.8% of patients completing the Maintenance Phase in the lacosamide 200, 400 and 600 mg/day groups, respectively, experienced no seizures throughout the entire Maintenance Phase (placebo group = 0.9%). The mean change from baseline in the percentage of seizure-free days in patients entering the Maintenance Phase for the phase II/III pool was 8.0%, 11.6% and 14.7% with lacosamide 200 (p =0.077), 400 (p<0.001) and 600 (p<0.001) mg/day groups, respectively, compared with 6.1% in the placebo group.

The onset of efficacy relative to placebo was evident by the first week of treatment with lacosamide. Efficacy was similar in lacosamide-treated patients reporting prior surgical intervention for epilepsy compared to lacosamidetreated patients with no prior surgical intervention. Lacosamide showed a reduction in seizures, regardless of the concomitant AEDs used. The preferred pharmacokinetic-pharmacodynamic model (Emax) supported the therapeutic dose range of lacosamide, and no additional safety concerns were identified in the phase II/III pooled analysis.

Conclusions: Results of these a priori-defined and post hoc pooled data analyses from phase II/III trials demonstrate that lacosamide effectively reduces seizures in patients at all three dosages evaluated with an early onset of efficacy, regardless of patient surgical history and concomitant AED regimen.

References

  1. 1.
    Bravata DM, Olkin I. Simple pooling versus combining in meta-analysis. Eval Health Prof 2001 Jun; 24(2): 218–30PubMedCrossRefGoogle Scholar
  2. 2.
    VIMPAT® (lacosamide): US prescribing information. Smyrna (GA): UCB, Inc., 2008Google Scholar
  3. 3.
    VIMPAT®: summary of product characteristics for lacosamide. Belgium: UCB Pharma, S.A., 2008Google Scholar
  4. 4.
    Beyreuther BK, Freitag J, Heers C, et al. Lacosamide: a review of preclinical properties. CNS Drug Rev 2007; 13(1): 21–42PubMedCrossRefGoogle Scholar
  5. 5.
    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 Jul; 48(7): 1308–17PubMedCrossRefGoogle Scholar
  6. 6.
    Halász P, Kälviäinen R, Mazurkiewicz-Beldzińska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009 Mar; 50(3): 443–53PubMedCrossRefGoogle Scholar
  7. 7.
    Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia 2010; 51(6): 958–67PubMedCrossRefGoogle Scholar
  8. 8.
    Biton V, Fountain NB, Rosenow F, et al. Safety and tolerability of lacosamide: a summary of adverse events in epilepsy clinical trials [abstract]. Neurology 2009; 72(11 Suppl. 1): A225Google Scholar
  9. 9.
    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 Jan; 9(1): 33–42PubMedCrossRefGoogle Scholar
  10. 10.
    Chung SS. Lacosamide: new adjunctive treatment option for partial-onset seizures. Expert Opin Pharmacother 2010 Jun; 11(9): 1595–602PubMedCrossRefGoogle Scholar
  11. 11.
    Ben-Menachem E, Chung S, Rudd D, et al. Evaluation of lacosamide efficacy in subjects with partial-onset seizures across the dose range used in phase II/III clinical trials [abstract]. Neurology 2009 Jun 28–Jul 2; 72(11 Suppl. 1): A329Google Scholar
  12. 12.
    French J, Brodie M, Hebert D, et al. Evaluation of seizure freedom and 75% responder rates with lacosamide in subjects with partial-onset seizures in phase II/III clinical trials. Innsbruck Colloquium on Status Epilepticus; 2009 Apr 2–4; InnsbruckGoogle Scholar
  13. 13.
    Gazzola DM, Balcer LJ, French JA. Seizure-free outcome in randomized add-on trials of the new antiepileptic drugs. Epilepsia 2007 Jul; 48(7): 1303–7PubMedCrossRefGoogle Scholar
  14. 14.
    Sperling M, Rudd D, Hebert D, et al. Early onset of efficacy in the initial weeks of treatment with lacosamide: a pooled analysis of three phase II/III trials. Neurology 2009; 72(11 Suppl. 1): A352Google Scholar
  15. 15.
    Benbadis S, Elger C, Hebert D, et al. Efficacy of adjunctive lacosamide in patients with partial-onset seizures and prior surgical interventions for epilepsy. American Epilepsy Society (AES) 63rd Annual Scientific Conference; 2009 Dec 4–8; Boston (MA)Google Scholar
  16. 16.
    Rosenfeld WRD, Hebert D, Doty P. Lacosamide efficacy is independent of concomitant AED(s) treatment [abstract]. Neurology 2009; 72(11 Suppl. 1): A353Google Scholar
  17. 17.
    Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology 2008 Jan 1; 70(1): 54–65PubMedCrossRefGoogle Scholar
  18. 18.
    Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsychiatr Dis Treat 2008 Jun; 4(3): 507–23PubMedCrossRefGoogle Scholar
  19. 19.
    Chung S. Third-generation antiepileptic drugs for partialonset seizures: lacosamide, retigabine, and eslicarbazepine. Eur Neurol J 2009; 1(1): 1–11Google Scholar
  20. 20.
    Cretin B, Hirsch E. Adjunctive antiepileptic drugs in adult epilepsy: how the first add-on could be the last. Expert Opin Pharmacother 2010 May; 11(7): 1053–67PubMedCrossRefGoogle Scholar
  21. 21.
    Gil-Nagel A, Zaccara G, Baldinetti F, et al. Add-on treatment with pregabalin for partial seizures with or without generalisation: pooled data analysis of four randomised placebo-controlled trials. Seizure 2009 Apr; 18(3): 184–92PubMedCrossRefGoogle Scholar
  22. 22.
    Peeters K, Adriaenssen I, Wapenaar R, et al. A pooled analysis of adjunctive topiramate in refractory partial epilepsy. Acta Neurol Scand 2003 Jul; 108(1): 9–15PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Steve Chung
    • 1
  • Elinor Ben-Menachem
    • 2
  • Michael R. Sperling
    • 3
  • William Rosenfeld
    • 4
  • Nathan B. Fountain
    • 5
  • Selim Benbadis
    • 6
  • David Hebert
    • 7
  • Jouko Isojärvi
    • 7
  • Pamela Doty
    • 7
  1. 1.Barrow Neurological InstituteSt. Joseph’s Hospital and Medical CenterPhoenixUSA
  2. 2.Sahlgrenska Academy University of GothenburgGothenburgSweden
  3. 3.Thomas Jefferson UniversityPhiladelphiaUSA
  4. 4.The Comprehensive Epilepsy Care Center for Children and AdultsSt. LouisUSA
  5. 5.University of VirginiaCharlottesvilleUSA
  6. 6.Tampa General HospitalUniversity of South FloridaTampaUSA
  7. 7.SCHWARZ Biosciences (a member of the UCB Group)RaleighUSA

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