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Efficacy of lacosamide by focal seizure subtype
Epilepsy Research (2014) 108, 1392—1398
journal homepage: www.elsevier.com/locate/epilepsyres
Efficacy of lacosamide by focal seizure subtype Michael R. Sperling a,∗, Felix Rosenow b, Edward Faught c, David Hebert d, Pamela Doty d, Jouko Isojärvi d,1 a
Thomas Jefferson University, Department of Neurology, 901 Walnut St., 4th floor, Philadelphia, PA 19107, USA b Philipps-University, Department of Neurology, Marburg, DE, USA c Emory University, Department of Neurology, Atlanta, GA, USA d UCB Pharma, 8010 Arco Corporate Dr., Suite 100, Raleigh, NC 27617, USA Received 23 October 2013; received in revised form 30 May 2014; accepted 17 June 2014 Available online 6 July 2014
KEYWORDS Antiepileptic drug; Lacosamide; Focal seizures; Partial onset seizures; Complex partial seizures; Secondarily generalized seizures
Summary The purpose of this post hoc exploratory analysis was to determine the effects of the antiepileptic drug, lacosamide, on focal (partial-onset) seizure subtypes. Patient data from the three lacosamide pivotal trials were grouped and pooled by focal seizure subtype at Baseline: simple partial seizures (SPS), complex partial seizures (CPS), and secondarily generalized partial seizures (SGPS). Both efficacy outcomes (median percent change from Baseline to Maintenance Phase in seizure frequency per 28 days and the proportion of patients experiencing at least a 50% reduction in seizures) were evaluated by lacosamide dose (200, 400, or 600 mg/day) compared to placebo for each seizure subtype. An additional analysis was performed to determine whether a shift from more severe focal seizure subtypes to less severe occurred upon treatment with lacosamide. In patients with CPS or SGPS at Baseline, lacosamide 400 mg/day (maximum recommended daily dose) and 600 mg/day reduced the frequency of CPS and SGPS compared to placebo. Likewise, a proportion of patients with CPS and SGPS at Baseline experienced at least a
∗
Corresponding author. Tel.: +1 215 955 1222; fax: +1 215 955 0606. E-mail addresses: [email protected] (M.R. Sperling), [email protected] (F. Rosenow), [email protected] (E. Faught), [email protected] (D. Hebert), [email protected] (P. Doty), jouko.isojarvi@oulu.fi (J. Isojärvi). 1 Present address: Lundbeck, 4 Parkway North, Deerfield, IL 60015, USA. http://dx.doi.org/10.1016/j.eplepsyres.2014.06.004 0920-1211/© 2014 Elsevier B.V. All rights reserved.
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50% reduction in the frequency of CPS and SGPS (≥50% responder rate) in the lacosamide 400 and 600 mg/day groups compared with placebo. For both outcomes, numerically greatest responses were observed in the lacosamide 600 mg/day group among patients with SGPS at Baseline. In patients with SPS at Baseline, no difference between placebo and lacosamide was observed for either efficacy outcome. An additional exploratory analysis suggests that in patients with SPS at Baseline, CPS and SGPS may have been shifted to less severe SPS upon treatment with lacosamide. The results of these exploratory analyses revealed reductions in CPS and SGPS frequency with adjunctive lacosamide. Reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS by effective treatment. © 2014 Elsevier B.V. All rights reserved.
Introduction
Methods
The treatment of epilepsy can be as complex as the disorder itself, often requiring the use of more than one antiepileptic drug (AED). Though newer AEDs may offer better tolerability than older AEDs (including carbamazepine, phenytoin, and valproate), as many as 30% of patients with focal epilepsy remain resistant to treatment (Mohanraj and Brodie, 2003). Treatment decisions are guided by a number of factors, including the type of seizure (Cretin and Hirsch, 2010; Privitera, 2011). Thus, differentiating between focal or generalized onset seizures has important clinical implications (Ferrie, 2005). Lacosamide is a mechanistically distinct AED used for the adjunctive treatment of adults with focal (partial-onset) seizures (≥17 years of age in the US, ≥16 years of age in the EU). The approval of lacosamide (200 or 400 mg/day) was based on positive results from three similarly designed multicenter, randomized, double-blind, placebo-controlled pivotal trials (Ben-Menachem et al., 2007; Chung et al., 2010; Halász et al., 2009). The primary outcomes of these and other AED registration trials are designed from a regulatory perspective and though necessary and informative in this context, the outcomes of such trials may not directly address questions that are relevant to everyday clinical practice (Faught, 2012), including those regarding treatment decisions based on an individual patient’s seizure subtype. There is a hierarchy of focal seizure severity, ranging from simple partial to complex partial to secondarily generalized. As the risk for serious consequences increases with increasing severity (Baker, 2002; Berg et al., 2010; Leidy et al., 1999), control of focal seizures—–particularly the most severe subtypes—–is an important clinical goal. To develop a fuller picture of the therapeutic benefits of lacosamide in the treatment of patients with focal seizures, an exploratory analysis was conducted to determine possible differential effects of lacosamide based on focal seizure subtypes, with a particular emphasis on patients who experienced complex partial seizures (CPS) and secondarily generalized partial seizures (SGPS) at Baseline of the pivotal Phase II/III trials. Though none of the pivotal trials were powered to determine differential effects of lacosamide on the various seizure subtypes by dose, the analysis of efficacy by seizure type was a priori defined in the individual trial protocols and was replicated in this pooled analysis.
Lacosamide pivotal trials Full details of the individual pivotal trials have been published (Ben-Menachem et al., 2007; Chung et al., 2010; Halász et al., 2009). Briefly, lacosamide was titrated weekly over a period of 4 or 6 weeks in 100 mg increments to the assigned target dose (200, 400, or 600 mg/day). Adult patients with a diagnosis of epilepsy with partial-onset seizures according to the International Classification of Epileptic Seizures (ILAE, 1981) were included. Patients were required to have at least a 2-year history of partial-onset seizures despite prior therapy with at least two AEDs (concurrently or sequentially). In the 8-week period before Baseline and during the 8-week Baseline Phase, patients were to have had at least four partial-onset seizures (either simple partial (SPS) with motor signs, complex partial (CPS), or secondarily generalized (SGPS) seizures per 28 days on average with no seizure-free period longer than 21 days. Patients taking one to three concomitant AEDs (one to two in trial SP667) with or without stable vagus nerve stimulation were maintained on their target lacosamide dose or placebo for a 12-week Maintenance Phase followed by either a 2-week blinded transition to 200 mg/day lacosamide (if entering an open-label extension trial) or a 2—3-week taper off trial medication. The primary efficacy variables assessed in the individual studies were: (1) change in partial seizure frequency per 28 days from Baseline to the Maintenance Phase and (2) the proportion of patients experiencing a 50% or greater reduction in seizure frequency from Baseline to Maintenance Phase (50% responder rate).
Analysis Given the similar trial designs and similar patient eligibility criteria, data from the three lacosamide pivotal trials were pooled. The exploratory analyses presented here evaluated the effect of lacosamide on different types of focal seizures by grouping patients according to seizure subtype at Baseline: all SPS (including those with or without focal motor symptoms), CPS, and SGPS (which may be generalized tonic, clonic, tonic—clonic). Patients could experience more than one seizure subtype at Baseline and could therefore be included in more than one subtype group (i.e., the grouping of patients based on Baseline seizure subtypes was
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Figure 1 Exploratory analyses of the pooled pivotal trial data by focal seizure subtype. a Patients could experience more than one type of focal seizure subtype at Baseline and therefore could be counted in more than one group. BL, baseline; CPS, complex partial seizures; MP, maintenance phase; SGPS, secondarily generalized partial seizures; SPS, simple partial seizures.
not mutually exclusive). Patients who did not have SGPS at Baseline may have had a history of SGPS. Seizure type and frequency were recorded by patients or caregivers in seizure diaries. Efficacy variables were analyzed by randomized dose assignment using an intention-to-treat (ITT) approach, which included all patients who received at least one dose of trial medication and had at least one post-Baseline efficacy assessment. The ITT approach was chosen as it is the most conservative analysis since it includes non-responders who discontinued treatment and was used for the primary outcomes of the included studies. For analysis of the efficacy outcomes by focal seizure subtype, inferential statistics are presented for each lacosamide dose compared to placebo. The grouping of patients by focal seizure subtype at Baseline (Fig. 1, row I) provides a visual roadmap for the efficacy analyses presented in this report. Since patients with SGPS at Baseline could also experience CPS or SPS, efficacy of lacosamide with respect to CPS, and SPS was examined in patients included in the SGPS group (Fig. 1, row II). To further examine the effect of lacosamide on the more severe seizure subtypes, efficacy of lacosamide for SPS and CPS was determined in patients who had SGPS at Baseline, but achieved freedom from that seizure subtype during the Maintenance Phase (Fig. 1, row III). An additional exploratory analysis was also conducted to investigate whether a shift from more severe to less severe seizure subtypes occurred upon treatment with lacosamide.
Results Patients Of the 1294 patients in the three Phase II/III pivotal trials (Ben-Menachem et al., 2007; Chung et al., 2010; Halász et al., 2009), 935 were randomized to lacosamide (Table 1). Overall, 75.9% of patients randomized to lacosamide
completed the trial compared with 88.3% of placebo patients. Overall, the patients were considered difficult to treat as 77.4% had used four or more lifetime AEDs. Most patients (84.4%) were receiving two or three concomitant AEDs; the most frequently used were carbamazepine (35.2%), lamotrigine (31.2%), levetiracetam (29.0%), valproate (23.6%), topiramate (22.3%), oxcarbazepine (17.8%), and phenytoin (14.1%). At Baseline, 416 patients had SPS, 1087 had CPS, and 540 had SGPS (Fig. 1; patients with more than one Baseline seizure subtype could be counted in more than one group). A total of 659 patients of the 1294 included in the pivotal trials had only one type of seizure at Baseline: SPS-only, 5.4% (n = 70/1294); CPS-only, 38.7% (n = 501/1294); and, SGPSonly, 6.8% (n = 88/1294) (Fig. 1). Of the 41.7% (n = 540/1294) of patients with SGPS during Baseline, 87.4% (n = 472/540) entered the Maintenance Phase, 93.2% (n = 440/472) completed the Maintenance Phase, and 22.0% (n = 97/440) of those completers were free from SGPS during the Maintenance Phase. Of the 58.3% (n = 754/1294) of patients who did not have SGPS at Baseline, 8.4% (n = 63/754) experienced SGPS post-Baseline. Fifty-eight of the 63 patients had a history of SGPS prior to study entry.
Efficacy Efficacy by Baseline seizure subtype Treatment with lacosamide 400 and 600 mg/day significantly reduced CPS and SGPS on both efficacy outcomes assessed. For patients with CPS during Baseline (Fig. 1, row I), median percent reductions in CPS per 28 days from Baseline to the Maintenance Phase were: 34.1% (P = 0.24), 40.8% (P < 0.01), and 41.9% (P < 0.01) for the lacosamide 200, 400, and 600 mg/day groups versus 22.4% for placebo (Fig. 2A). For patients with SGPS during Baseline (Fig. 1, row I), median percent reductions in SGPS per 28 days from Baseline to the Maintenance Phase were: 50.0% (P = 0.50),
Efficacy of lacosamide by focal seizure subtype Table 1
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Patient demographics and Baseline characteristics. Placebo (n = 359)
200 mg/day (n = 267) Age, mean years Male, % Time since diagnosis, mean years Lifetime AEDs, % 1—3 4—6 ≥7 Missing Concomitant AEDs, % 1 2 3
Total (N = 1294)
Lacosamide 400 mg/day (n = 466)
600 mg/day (n = 202)
38.5 51.5 23.4
38.1 50.2 23.8
39.2 47.6 23.9
38.1 45.5 23.5
38.6 48.9 23.7
21.7 32.9 44.6 0.8
22.8 30.7 44.9 1.5
23.6 32.0 43.8 0.6
15.8 33.7 50.0 0.5
21.7 32.2 45.2 0.9
16.7 58.8 24.5
12.4 62.9 24.7
16.7 59.9 23.4
14.9 74.3 10.9
15.5 62.4 22.0
Type of seizure during Baseline, #patients (%)a SPS 110 (30.6) CPS 295 (82.2) SGPS 164 (45.7) SPS-only 24 (6.7) CPS-only 128 (35.7) SGPS-only 28 (7.8)
86 (32.2) 229 (85.8) 106 (39.7) 18 (6.7) 108 (40.4) 9 (3.4)
141 (30.3) 398 (85.4) 185 (39.7) 13 (2.8) 194 (41.6) 38 (8.2)
79 (39.1) 165 (81.7) 85 (42.1) 15 (7.4) 71 (35.1) 13 (6.4)
416 (32.1) 1087 (84.0) 540 (41.7) 70 (5.4) 501 (38.7) 88 (6.8)
CPS, complex partial seizures; SGPS, secondarily generalized partial seizures; SPS, simple partial seizures. a Patients could experience more than one focal seizure subtype at Baseline and therefore could be counted in more than one group.
55.6% (P < 0.01), and 85.9% (P < 0.01) for the lacosamide 200, 400, and 600 mg/day groups versus 32.5% for placebo (Fig. 2A). The ≥50% responder rates from Baseline to the Maintenance Phase for patients with CPS during Baseline were 35.8% (OR: 1.2, P = 0.29), 43.0% (OR: 1.9, P < 0.01), and 41.8% (OR: 1.9, P < 0.01) for the lacosamide 200, 400, and 600 mg/day groups compared to placebo (29.2%; Fig. 2B). For patients with SGPS during Baseline, ≥50% responder rates from Baseline to the Maintenance Phase were 50.9% (OR: 1.7, P = 0.07), 53.5% (OR: 2.0, P < 0.01), 64.7% (OR: 3.2, P < 0.01) for lacosamide 200, 400, and 600 mg/day, respectively, compared to placebo (36.6%; Fig. 2B). The reduction in SGPS compared with placebo appeared to be doserelated, with the greatest response to treatment occurring in the lacosamide 600 mg/day group; however, a statistical comparison between lacosamide treatment groups is not appropriate since the studies were not designed or powered for such comparisons. The reduction of CPS with lacosamide 400 and 600 mg/day did not appear to be dose-related, though inferential statistics cannot be performed to confirm this observation for the same reason as stated above. For patients with SPS during Baseline (Fig. 1, row I), median percent reductions in SPS per 28 days from Baseline to the Maintenance Phase were comparable to placebo: 30.4% (P = 0.56; n = 86), 31.3% (P = 0.25; n = 141), and 23.1% (P = 0.39; n = 79) for the lacosamide 200, 400, and 600 mg/day groups versus 34.4% for placebo (n = 110). The ≥50% responder rates from Baseline to the Maintenance Phase for SPS in patients with SPS during Baseline were 38.4%
(OR: 1.0, P = 0.96, n = 86), 36.2% (OR: 0.8, P = 0.46; n = 141), and 38.0% (OR: 0.9, P = 0.79, n = 79) for the lacosamide 200, 400, and 600 mg/day groups and were comparable with placebo (39.1%, n = 110). Efficacy in patients with SGPS at Baseline The effects of lacosamide on CPS and SPS were further examined in the 540 patients who experienced SGPS at Baseline who were also experiencing CPS or SPS (Fig. 1, row II). During the Maintenance Phase, lacosamide 200 and 400 mg/day numerically reduced CPS frequency per 28 days, with median percent reductions of 36.0% (P = 0.68, n = 86) and 35.5% (P = 0.04, n = 130), respectively, versus 22.9% for placebo (n = 124); no treatment effect was observed with lacosamide 600 mg/day (P = 0.95, n = 63; Fig. 3). A numerical increase in ≥50% responder rates for CPS was observed in the lacosamide 200 mg/day (39.5%, OR: 1.3, P = 0.46, n = 86) and 400 mg/day groups (40.0%, OR: 1.3, P = 0.36, n = 130) compared with placebo (33.9%, n = 124); the ≥50% responder rate for patients in the lacosamide 600 mg/day group was 31.7% (OR: 0.8, P = 0.64). In the same subset of patients, the median percent reduction in SPS per 28 days from Baseline to the Maintenance Phase was numerically increased versus placebo (43.5%; n = 43) with lacosamide 200 mg/day (60.8%; P = 0.33; n = 33) and no treatment effect was observed with lacosamide 400 mg/day (37.1%; P = 0.86; n = 54) and 600 mg/day (0.4%; P = 0.37; n = 33). Similar pattern was observed in the ≥50% responder rates for SPS. In the lacosamide 200 mg/day
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Figure 3 Efficacy in patients with SGPS at Baseline. Only frequency of CPS was used in the analysis; Maintenance Phase includes data for the Titration Phase for patients who discontinued prior to entering the Maintenance Phase.
with 33.3, 59.4, and 50.0% of patients in the lacosamide 200, 400, and 600 mg/day groups having at least a 50% reduction in the frequency of CPS versus 26.1% for placebo. On both efficacy outcomes assessed, no numerical difference between the lacosamide 400 and 600 mg/day groups could be detected. No clear treatment effect of lacosamide on SPS was observed among these patients. Median percent reductions in SPS were 86.0% (n = 6), 30.7% (n = 12), and 0.4% (n = 7) for the lacosamide 200, 400, and 600 mg/day groups versus 60.9% (n = 6) for placebo; the ≥50% responder rates were 83.3, 50.0, and 42.9% for the lacosamide 200, 400, and 600 mg/day groups versus 66.7% for placebo. Figure 2 Efficacy by Baseline seizure subtype from Baseline to Maintenance. (A) Reduction in seizure frequency per 28 days. (B) Response to treatment of ≥50%. Only seizure frequencies of the specified seizure subtypes are used in the analysis; Maintenance Phase includes data for patients who discontinued during the Titration Phase.
Additional exploratory analysis In order to determine whether a shift in seizure subtype (from more severe to less severe) with lacosamide
group, a numerical increase in ≥50% responder rates for SPS was observed compared with placebo (54.5% [OR: 1.9, P = 0.24, n = 33] versus 46.5% [n = 43]). The ≥50% responder rates in the 400 and 600 mg/day groups were 42.6% (OR: 0.8, P = 0.56, n = 54) and 30.3% (OR: 0.4, P = 0.13, n = 33), respectively, compared with the placebo group. Efficacy in patients achieving SGPS freedom Efficacy was examined for the subset of patients with SGPS during Baseline who completed the Maintenance Phase and achieved freedom from SGPS during the Maintenance Phase (Fig. 1, row III). In these patients, lacosamide 400 and 600 mg/day reduced the frequency of CPS, as median percent reductions in the frequency of CPS were 26.2, 58.4, and 55.8% for the lacosamide 200, 400, and 600 mg/day groups versus 20.9% for placebo (Fig. 4). An increase in the proportion of 50% responders with lacosamide was also observed,
Figure 4
Efficacy in patients achieving SGPS freedom.
Efficacy of lacosamide by focal seizure subtype treatment might have influenced the results observed in patients with SPS at Baseline, an additional exploratory analysis was conducted. This analysis included patients entering the Maintenance Phase who had SPS during Baseline and a ≥25 or ≥50% reduction in CPS or SGPS in the Maintenance Phase. In lacosamide-treated patients (all doses combined) who had at least a 25% reduction in CPS or SGPS during the Maintenance Phase (n = 147), there was a 5.5% increase in SPS frequency compared with placebo (P = 0.78). For those with at least a 50% reduction in CPS or SGPS during the Maintenance Phase (n = 94), a 9.0% increase in SPS frequency was detected over placebo (P = 0.76), consistent with transformation of CPS and SGPS to the SPS subtype.
Discussion In the exploratory analyses presented here, the effects of lacosamide on focal seizure subtypes were evaluated in patients who participated in the three lacosamide Phase II/III pivotal trials. Nearly half (42%) of the patients in the pooled population experienced SGPS; data from these patients were used for additional analyses to further characterize the benefit of lacosamide on CPS and SPS. An additional exploratory analysis on patients with SPS at Baseline was performed to identify a potential shift from more severe to less severe seizure subtypes resulting from lacosamide treatment. Like other clinical trials of newer AEDs, the lacosamide pivotal studies were designed to detect efficacy and safety of lacosamide in a population of patients with focal seizures and were not powered to detect treatment effects based on focal seizure subtype. While efficacy outcomes that meet the requirements of regulatory agencies are both valid and useful, these outcomes may not answer all clinical questions regarding the most effective treatment for the specific types of focal seizures that are most prevalent in an individual patient. To that end, post hoc and exploratory analyses of data derived from randomized, controlled trials coupled with clinical experience can provide useful insights into the most effective use of an AED. The results of these exploratory analyses revealed consistent reductions in CPS and SGPS frequency with lacosamide treatment (400 and 600 mg/day) with a dose-related effect apparent in SGPS. In this exploratory analysis, the effect of adjunctive lacosamide on SPS was comparable with placebo. No significant reduction in SPS compared to placebo has also been reported in studies with lamotrigine (Boas et al., 1996), gabapentin (Leach et al., 1997), and levetiracetam (Cereghino et al., 2000). The mechanism for this phenomenon remains unclear, however potential hypothesis/explanation could be that reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS following effective treatment. In that circumstance, an AED may not be less effective in SPS than CPS or SGPS, but rather the amelioration of seizure severity may interfere with the interpretation of efficacy on SPS. Results from the additional exploratory analysis that was conducted on the group of patients with SPS at Baseline indicated an increased frequency of SPS with a concurrent decrease in CPS and SGPS. Though it cannot be proved that the increase in SPS frequency is a direct result of the same
1397 patients experiencing a decrease in either CPS or SGPS, the results are consistent with a shift from more severe seizures to less severe in these lacosamide-treated patients. Such a shift in seizure subtypes would reduce the ability to demonstrate an effect of lacosamide on SPS. Clinical experience has revealed tremendous variability regarding the consequences that different focal seizure subtypes have on individual patients, and the benefit a patient derives from an AED might depend as much on changes in seizure severity as on reductions in seizure frequency. Reductions in seizure severity, particularly for SGPS, may have an important impact on multiple medical and psychosocial domains including morbidity, mortality, and quality of life (Sperling, 2004). Though the benefits of alleviating seizure severity may be difficult to assess in brief, timelimited studies, such treatment effects may decrease the frequency of accidents, injury, and death, lessen direct and indirect healthcare costs, and improve both cognitive performance and employment status (Baker, 2002; Cockerell et al., 1994; Gilliam et al., 2005; Hamer et al., 2006; Lhatoo and Sander, 2005; Strzelczyk et al., 2012). An AED that reduces SGPS would be clinically beneficial, particularly as the presence of poorly controlled primary or secondarily generalized tonic-clonic seizures is the main predictor of SUDEP (Duncan and Brodie, 2011; Hesdorffer et al., 2011; Surges et al., 2010; Tomson et al., 2008). Despite the fact that the lacosamide pivotal trials were powered to detect the effect of lacosamide on combined partial seizures rather than by focal seizure subtype, the results of these exploratory analyses revealed consistent reductions in CPS and SGPS frequency with adjunctive lacosamide. Reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS by effective treatment.
Conflicts of interest statement Dr. M. Sperling has received research support from UCB Pharma, Lundbeck, Eisai, SK Life Sciences, Sunovion, Vertex, Visualise, and Medtronics, and consulted for Acorda Therapeutics, UCB Pharma, and electroCore. Within the last 2 years, Dr. F. Rosenow has received: consulting fees from GSK, EISAI, UCB Pharma, and Pfizer; speakers honoraria from UCB Pharma, GSK, EISAI, Desitin, and Medtronic; and, educational grants from Nihon-Kohden, UCB Pharma, Medtronics, Cyberonics, and Cerbomed. Dr. E. Faught has received consulting fees from Lundbeck, Medivation, Sunovion, UCB Pharma, and Vertex, honoraria for service on data monitoring boards from Eisai, Lundbeck, and SK Life Sciences, and research support from Cyberonics, GlaxoSmithKline, and UCB Pharma. Drs. D. Hebert and P. Doty are employees of UCB Pharma. Dr. J. Isojärvi was an employee of UCB Pharma at the time of the analyses. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Acknowledgements The studies and exploratory analysis of pooled trial data was funded by UCB Pharma. Writing support was provided
1398 by Kristen A. Andersen, Ph.D. of Prescott Medical Communications Group in Chicago, Illinois, USA. Editorial support was provided by Jonathon Gibbs of Evidence Scientific Solutions, Horsham, UK. Publication management in the form of publication coordination was provided by Jesse Fishman, PharmD, and Azita Tofighy, PhD, employees of UCB Pharma.
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journal homepage: www.elsevier.com/locate/epilepsyres
Efficacy of lacosamide by focal seizure subtype Michael R. Sperling a,∗, Felix Rosenow b, Edward Faught c, David Hebert d, Pamela Doty d, Jouko Isojärvi d,1 a
Thomas Jefferson University, Department of Neurology, 901 Walnut St., 4th floor, Philadelphia, PA 19107, USA b Philipps-University, Department of Neurology, Marburg, DE, USA c Emory University, Department of Neurology, Atlanta, GA, USA d UCB Pharma, 8010 Arco Corporate Dr., Suite 100, Raleigh, NC 27617, USA Received 23 October 2013; received in revised form 30 May 2014; accepted 17 June 2014 Available online 6 July 2014
KEYWORDS Antiepileptic drug; Lacosamide; Focal seizures; Partial onset seizures; Complex partial seizures; Secondarily generalized seizures
Summary The purpose of this post hoc exploratory analysis was to determine the effects of the antiepileptic drug, lacosamide, on focal (partial-onset) seizure subtypes. Patient data from the three lacosamide pivotal trials were grouped and pooled by focal seizure subtype at Baseline: simple partial seizures (SPS), complex partial seizures (CPS), and secondarily generalized partial seizures (SGPS). Both efficacy outcomes (median percent change from Baseline to Maintenance Phase in seizure frequency per 28 days and the proportion of patients experiencing at least a 50% reduction in seizures) were evaluated by lacosamide dose (200, 400, or 600 mg/day) compared to placebo for each seizure subtype. An additional analysis was performed to determine whether a shift from more severe focal seizure subtypes to less severe occurred upon treatment with lacosamide. In patients with CPS or SGPS at Baseline, lacosamide 400 mg/day (maximum recommended daily dose) and 600 mg/day reduced the frequency of CPS and SGPS compared to placebo. Likewise, a proportion of patients with CPS and SGPS at Baseline experienced at least a
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Corresponding author. Tel.: +1 215 955 1222; fax: +1 215 955 0606. E-mail addresses: [email protected] (M.R. Sperling), [email protected] (F. Rosenow), [email protected] (E. Faught), [email protected] (D. Hebert), [email protected] (P. Doty), jouko.isojarvi@oulu.fi (J. Isojärvi). 1 Present address: Lundbeck, 4 Parkway North, Deerfield, IL 60015, USA. http://dx.doi.org/10.1016/j.eplepsyres.2014.06.004 0920-1211/© 2014 Elsevier B.V. All rights reserved.
Efficacy of lacosamide by focal seizure subtype
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50% reduction in the frequency of CPS and SGPS (≥50% responder rate) in the lacosamide 400 and 600 mg/day groups compared with placebo. For both outcomes, numerically greatest responses were observed in the lacosamide 600 mg/day group among patients with SGPS at Baseline. In patients with SPS at Baseline, no difference between placebo and lacosamide was observed for either efficacy outcome. An additional exploratory analysis suggests that in patients with SPS at Baseline, CPS and SGPS may have been shifted to less severe SPS upon treatment with lacosamide. The results of these exploratory analyses revealed reductions in CPS and SGPS frequency with adjunctive lacosamide. Reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS by effective treatment. © 2014 Elsevier B.V. All rights reserved.
Introduction
Methods
The treatment of epilepsy can be as complex as the disorder itself, often requiring the use of more than one antiepileptic drug (AED). Though newer AEDs may offer better tolerability than older AEDs (including carbamazepine, phenytoin, and valproate), as many as 30% of patients with focal epilepsy remain resistant to treatment (Mohanraj and Brodie, 2003). Treatment decisions are guided by a number of factors, including the type of seizure (Cretin and Hirsch, 2010; Privitera, 2011). Thus, differentiating between focal or generalized onset seizures has important clinical implications (Ferrie, 2005). Lacosamide is a mechanistically distinct AED used for the adjunctive treatment of adults with focal (partial-onset) seizures (≥17 years of age in the US, ≥16 years of age in the EU). The approval of lacosamide (200 or 400 mg/day) was based on positive results from three similarly designed multicenter, randomized, double-blind, placebo-controlled pivotal trials (Ben-Menachem et al., 2007; Chung et al., 2010; Halász et al., 2009). The primary outcomes of these and other AED registration trials are designed from a regulatory perspective and though necessary and informative in this context, the outcomes of such trials may not directly address questions that are relevant to everyday clinical practice (Faught, 2012), including those regarding treatment decisions based on an individual patient’s seizure subtype. There is a hierarchy of focal seizure severity, ranging from simple partial to complex partial to secondarily generalized. As the risk for serious consequences increases with increasing severity (Baker, 2002; Berg et al., 2010; Leidy et al., 1999), control of focal seizures—–particularly the most severe subtypes—–is an important clinical goal. To develop a fuller picture of the therapeutic benefits of lacosamide in the treatment of patients with focal seizures, an exploratory analysis was conducted to determine possible differential effects of lacosamide based on focal seizure subtypes, with a particular emphasis on patients who experienced complex partial seizures (CPS) and secondarily generalized partial seizures (SGPS) at Baseline of the pivotal Phase II/III trials. Though none of the pivotal trials were powered to determine differential effects of lacosamide on the various seizure subtypes by dose, the analysis of efficacy by seizure type was a priori defined in the individual trial protocols and was replicated in this pooled analysis.
Lacosamide pivotal trials Full details of the individual pivotal trials have been published (Ben-Menachem et al., 2007; Chung et al., 2010; Halász et al., 2009). Briefly, lacosamide was titrated weekly over a period of 4 or 6 weeks in 100 mg increments to the assigned target dose (200, 400, or 600 mg/day). Adult patients with a diagnosis of epilepsy with partial-onset seizures according to the International Classification of Epileptic Seizures (ILAE, 1981) were included. Patients were required to have at least a 2-year history of partial-onset seizures despite prior therapy with at least two AEDs (concurrently or sequentially). In the 8-week period before Baseline and during the 8-week Baseline Phase, patients were to have had at least four partial-onset seizures (either simple partial (SPS) with motor signs, complex partial (CPS), or secondarily generalized (SGPS) seizures per 28 days on average with no seizure-free period longer than 21 days. Patients taking one to three concomitant AEDs (one to two in trial SP667) with or without stable vagus nerve stimulation were maintained on their target lacosamide dose or placebo for a 12-week Maintenance Phase followed by either a 2-week blinded transition to 200 mg/day lacosamide (if entering an open-label extension trial) or a 2—3-week taper off trial medication. The primary efficacy variables assessed in the individual studies were: (1) change in partial seizure frequency per 28 days from Baseline to the Maintenance Phase and (2) the proportion of patients experiencing a 50% or greater reduction in seizure frequency from Baseline to Maintenance Phase (50% responder rate).
Analysis Given the similar trial designs and similar patient eligibility criteria, data from the three lacosamide pivotal trials were pooled. The exploratory analyses presented here evaluated the effect of lacosamide on different types of focal seizures by grouping patients according to seizure subtype at Baseline: all SPS (including those with or without focal motor symptoms), CPS, and SGPS (which may be generalized tonic, clonic, tonic—clonic). Patients could experience more than one seizure subtype at Baseline and could therefore be included in more than one subtype group (i.e., the grouping of patients based on Baseline seizure subtypes was
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Figure 1 Exploratory analyses of the pooled pivotal trial data by focal seizure subtype. a Patients could experience more than one type of focal seizure subtype at Baseline and therefore could be counted in more than one group. BL, baseline; CPS, complex partial seizures; MP, maintenance phase; SGPS, secondarily generalized partial seizures; SPS, simple partial seizures.
not mutually exclusive). Patients who did not have SGPS at Baseline may have had a history of SGPS. Seizure type and frequency were recorded by patients or caregivers in seizure diaries. Efficacy variables were analyzed by randomized dose assignment using an intention-to-treat (ITT) approach, which included all patients who received at least one dose of trial medication and had at least one post-Baseline efficacy assessment. The ITT approach was chosen as it is the most conservative analysis since it includes non-responders who discontinued treatment and was used for the primary outcomes of the included studies. For analysis of the efficacy outcomes by focal seizure subtype, inferential statistics are presented for each lacosamide dose compared to placebo. The grouping of patients by focal seizure subtype at Baseline (Fig. 1, row I) provides a visual roadmap for the efficacy analyses presented in this report. Since patients with SGPS at Baseline could also experience CPS or SPS, efficacy of lacosamide with respect to CPS, and SPS was examined in patients included in the SGPS group (Fig. 1, row II). To further examine the effect of lacosamide on the more severe seizure subtypes, efficacy of lacosamide for SPS and CPS was determined in patients who had SGPS at Baseline, but achieved freedom from that seizure subtype during the Maintenance Phase (Fig. 1, row III). An additional exploratory analysis was also conducted to investigate whether a shift from more severe to less severe seizure subtypes occurred upon treatment with lacosamide.
Results Patients Of the 1294 patients in the three Phase II/III pivotal trials (Ben-Menachem et al., 2007; Chung et al., 2010; Halász et al., 2009), 935 were randomized to lacosamide (Table 1). Overall, 75.9% of patients randomized to lacosamide
completed the trial compared with 88.3% of placebo patients. Overall, the patients were considered difficult to treat as 77.4% had used four or more lifetime AEDs. Most patients (84.4%) were receiving two or three concomitant AEDs; the most frequently used were carbamazepine (35.2%), lamotrigine (31.2%), levetiracetam (29.0%), valproate (23.6%), topiramate (22.3%), oxcarbazepine (17.8%), and phenytoin (14.1%). At Baseline, 416 patients had SPS, 1087 had CPS, and 540 had SGPS (Fig. 1; patients with more than one Baseline seizure subtype could be counted in more than one group). A total of 659 patients of the 1294 included in the pivotal trials had only one type of seizure at Baseline: SPS-only, 5.4% (n = 70/1294); CPS-only, 38.7% (n = 501/1294); and, SGPSonly, 6.8% (n = 88/1294) (Fig. 1). Of the 41.7% (n = 540/1294) of patients with SGPS during Baseline, 87.4% (n = 472/540) entered the Maintenance Phase, 93.2% (n = 440/472) completed the Maintenance Phase, and 22.0% (n = 97/440) of those completers were free from SGPS during the Maintenance Phase. Of the 58.3% (n = 754/1294) of patients who did not have SGPS at Baseline, 8.4% (n = 63/754) experienced SGPS post-Baseline. Fifty-eight of the 63 patients had a history of SGPS prior to study entry.
Efficacy Efficacy by Baseline seizure subtype Treatment with lacosamide 400 and 600 mg/day significantly reduced CPS and SGPS on both efficacy outcomes assessed. For patients with CPS during Baseline (Fig. 1, row I), median percent reductions in CPS per 28 days from Baseline to the Maintenance Phase were: 34.1% (P = 0.24), 40.8% (P < 0.01), and 41.9% (P < 0.01) for the lacosamide 200, 400, and 600 mg/day groups versus 22.4% for placebo (Fig. 2A). For patients with SGPS during Baseline (Fig. 1, row I), median percent reductions in SGPS per 28 days from Baseline to the Maintenance Phase were: 50.0% (P = 0.50),
Efficacy of lacosamide by focal seizure subtype Table 1
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Patient demographics and Baseline characteristics. Placebo (n = 359)
200 mg/day (n = 267) Age, mean years Male, % Time since diagnosis, mean years Lifetime AEDs, % 1—3 4—6 ≥7 Missing Concomitant AEDs, % 1 2 3
Total (N = 1294)
Lacosamide 400 mg/day (n = 466)
600 mg/day (n = 202)
38.5 51.5 23.4
38.1 50.2 23.8
39.2 47.6 23.9
38.1 45.5 23.5
38.6 48.9 23.7
21.7 32.9 44.6 0.8
22.8 30.7 44.9 1.5
23.6 32.0 43.8 0.6
15.8 33.7 50.0 0.5
21.7 32.2 45.2 0.9
16.7 58.8 24.5
12.4 62.9 24.7
16.7 59.9 23.4
14.9 74.3 10.9
15.5 62.4 22.0
Type of seizure during Baseline, #patients (%)a SPS 110 (30.6) CPS 295 (82.2) SGPS 164 (45.7) SPS-only 24 (6.7) CPS-only 128 (35.7) SGPS-only 28 (7.8)
86 (32.2) 229 (85.8) 106 (39.7) 18 (6.7) 108 (40.4) 9 (3.4)
141 (30.3) 398 (85.4) 185 (39.7) 13 (2.8) 194 (41.6) 38 (8.2)
79 (39.1) 165 (81.7) 85 (42.1) 15 (7.4) 71 (35.1) 13 (6.4)
416 (32.1) 1087 (84.0) 540 (41.7) 70 (5.4) 501 (38.7) 88 (6.8)
CPS, complex partial seizures; SGPS, secondarily generalized partial seizures; SPS, simple partial seizures. a Patients could experience more than one focal seizure subtype at Baseline and therefore could be counted in more than one group.
55.6% (P < 0.01), and 85.9% (P < 0.01) for the lacosamide 200, 400, and 600 mg/day groups versus 32.5% for placebo (Fig. 2A). The ≥50% responder rates from Baseline to the Maintenance Phase for patients with CPS during Baseline were 35.8% (OR: 1.2, P = 0.29), 43.0% (OR: 1.9, P < 0.01), and 41.8% (OR: 1.9, P < 0.01) for the lacosamide 200, 400, and 600 mg/day groups compared to placebo (29.2%; Fig. 2B). For patients with SGPS during Baseline, ≥50% responder rates from Baseline to the Maintenance Phase were 50.9% (OR: 1.7, P = 0.07), 53.5% (OR: 2.0, P < 0.01), 64.7% (OR: 3.2, P < 0.01) for lacosamide 200, 400, and 600 mg/day, respectively, compared to placebo (36.6%; Fig. 2B). The reduction in SGPS compared with placebo appeared to be doserelated, with the greatest response to treatment occurring in the lacosamide 600 mg/day group; however, a statistical comparison between lacosamide treatment groups is not appropriate since the studies were not designed or powered for such comparisons. The reduction of CPS with lacosamide 400 and 600 mg/day did not appear to be dose-related, though inferential statistics cannot be performed to confirm this observation for the same reason as stated above. For patients with SPS during Baseline (Fig. 1, row I), median percent reductions in SPS per 28 days from Baseline to the Maintenance Phase were comparable to placebo: 30.4% (P = 0.56; n = 86), 31.3% (P = 0.25; n = 141), and 23.1% (P = 0.39; n = 79) for the lacosamide 200, 400, and 600 mg/day groups versus 34.4% for placebo (n = 110). The ≥50% responder rates from Baseline to the Maintenance Phase for SPS in patients with SPS during Baseline were 38.4%
(OR: 1.0, P = 0.96, n = 86), 36.2% (OR: 0.8, P = 0.46; n = 141), and 38.0% (OR: 0.9, P = 0.79, n = 79) for the lacosamide 200, 400, and 600 mg/day groups and were comparable with placebo (39.1%, n = 110). Efficacy in patients with SGPS at Baseline The effects of lacosamide on CPS and SPS were further examined in the 540 patients who experienced SGPS at Baseline who were also experiencing CPS or SPS (Fig. 1, row II). During the Maintenance Phase, lacosamide 200 and 400 mg/day numerically reduced CPS frequency per 28 days, with median percent reductions of 36.0% (P = 0.68, n = 86) and 35.5% (P = 0.04, n = 130), respectively, versus 22.9% for placebo (n = 124); no treatment effect was observed with lacosamide 600 mg/day (P = 0.95, n = 63; Fig. 3). A numerical increase in ≥50% responder rates for CPS was observed in the lacosamide 200 mg/day (39.5%, OR: 1.3, P = 0.46, n = 86) and 400 mg/day groups (40.0%, OR: 1.3, P = 0.36, n = 130) compared with placebo (33.9%, n = 124); the ≥50% responder rate for patients in the lacosamide 600 mg/day group was 31.7% (OR: 0.8, P = 0.64). In the same subset of patients, the median percent reduction in SPS per 28 days from Baseline to the Maintenance Phase was numerically increased versus placebo (43.5%; n = 43) with lacosamide 200 mg/day (60.8%; P = 0.33; n = 33) and no treatment effect was observed with lacosamide 400 mg/day (37.1%; P = 0.86; n = 54) and 600 mg/day (0.4%; P = 0.37; n = 33). Similar pattern was observed in the ≥50% responder rates for SPS. In the lacosamide 200 mg/day
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Figure 3 Efficacy in patients with SGPS at Baseline. Only frequency of CPS was used in the analysis; Maintenance Phase includes data for the Titration Phase for patients who discontinued prior to entering the Maintenance Phase.
with 33.3, 59.4, and 50.0% of patients in the lacosamide 200, 400, and 600 mg/day groups having at least a 50% reduction in the frequency of CPS versus 26.1% for placebo. On both efficacy outcomes assessed, no numerical difference between the lacosamide 400 and 600 mg/day groups could be detected. No clear treatment effect of lacosamide on SPS was observed among these patients. Median percent reductions in SPS were 86.0% (n = 6), 30.7% (n = 12), and 0.4% (n = 7) for the lacosamide 200, 400, and 600 mg/day groups versus 60.9% (n = 6) for placebo; the ≥50% responder rates were 83.3, 50.0, and 42.9% for the lacosamide 200, 400, and 600 mg/day groups versus 66.7% for placebo. Figure 2 Efficacy by Baseline seizure subtype from Baseline to Maintenance. (A) Reduction in seizure frequency per 28 days. (B) Response to treatment of ≥50%. Only seizure frequencies of the specified seizure subtypes are used in the analysis; Maintenance Phase includes data for patients who discontinued during the Titration Phase.
Additional exploratory analysis In order to determine whether a shift in seizure subtype (from more severe to less severe) with lacosamide
group, a numerical increase in ≥50% responder rates for SPS was observed compared with placebo (54.5% [OR: 1.9, P = 0.24, n = 33] versus 46.5% [n = 43]). The ≥50% responder rates in the 400 and 600 mg/day groups were 42.6% (OR: 0.8, P = 0.56, n = 54) and 30.3% (OR: 0.4, P = 0.13, n = 33), respectively, compared with the placebo group. Efficacy in patients achieving SGPS freedom Efficacy was examined for the subset of patients with SGPS during Baseline who completed the Maintenance Phase and achieved freedom from SGPS during the Maintenance Phase (Fig. 1, row III). In these patients, lacosamide 400 and 600 mg/day reduced the frequency of CPS, as median percent reductions in the frequency of CPS were 26.2, 58.4, and 55.8% for the lacosamide 200, 400, and 600 mg/day groups versus 20.9% for placebo (Fig. 4). An increase in the proportion of 50% responders with lacosamide was also observed,
Figure 4
Efficacy in patients achieving SGPS freedom.
Efficacy of lacosamide by focal seizure subtype treatment might have influenced the results observed in patients with SPS at Baseline, an additional exploratory analysis was conducted. This analysis included patients entering the Maintenance Phase who had SPS during Baseline and a ≥25 or ≥50% reduction in CPS or SGPS in the Maintenance Phase. In lacosamide-treated patients (all doses combined) who had at least a 25% reduction in CPS or SGPS during the Maintenance Phase (n = 147), there was a 5.5% increase in SPS frequency compared with placebo (P = 0.78). For those with at least a 50% reduction in CPS or SGPS during the Maintenance Phase (n = 94), a 9.0% increase in SPS frequency was detected over placebo (P = 0.76), consistent with transformation of CPS and SGPS to the SPS subtype.
Discussion In the exploratory analyses presented here, the effects of lacosamide on focal seizure subtypes were evaluated in patients who participated in the three lacosamide Phase II/III pivotal trials. Nearly half (42%) of the patients in the pooled population experienced SGPS; data from these patients were used for additional analyses to further characterize the benefit of lacosamide on CPS and SPS. An additional exploratory analysis on patients with SPS at Baseline was performed to identify a potential shift from more severe to less severe seizure subtypes resulting from lacosamide treatment. Like other clinical trials of newer AEDs, the lacosamide pivotal studies were designed to detect efficacy and safety of lacosamide in a population of patients with focal seizures and were not powered to detect treatment effects based on focal seizure subtype. While efficacy outcomes that meet the requirements of regulatory agencies are both valid and useful, these outcomes may not answer all clinical questions regarding the most effective treatment for the specific types of focal seizures that are most prevalent in an individual patient. To that end, post hoc and exploratory analyses of data derived from randomized, controlled trials coupled with clinical experience can provide useful insights into the most effective use of an AED. The results of these exploratory analyses revealed consistent reductions in CPS and SGPS frequency with lacosamide treatment (400 and 600 mg/day) with a dose-related effect apparent in SGPS. In this exploratory analysis, the effect of adjunctive lacosamide on SPS was comparable with placebo. No significant reduction in SPS compared to placebo has also been reported in studies with lamotrigine (Boas et al., 1996), gabapentin (Leach et al., 1997), and levetiracetam (Cereghino et al., 2000). The mechanism for this phenomenon remains unclear, however potential hypothesis/explanation could be that reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS following effective treatment. In that circumstance, an AED may not be less effective in SPS than CPS or SGPS, but rather the amelioration of seizure severity may interfere with the interpretation of efficacy on SPS. Results from the additional exploratory analysis that was conducted on the group of patients with SPS at Baseline indicated an increased frequency of SPS with a concurrent decrease in CPS and SGPS. Though it cannot be proved that the increase in SPS frequency is a direct result of the same
1397 patients experiencing a decrease in either CPS or SGPS, the results are consistent with a shift from more severe seizures to less severe in these lacosamide-treated patients. Such a shift in seizure subtypes would reduce the ability to demonstrate an effect of lacosamide on SPS. Clinical experience has revealed tremendous variability regarding the consequences that different focal seizure subtypes have on individual patients, and the benefit a patient derives from an AED might depend as much on changes in seizure severity as on reductions in seizure frequency. Reductions in seizure severity, particularly for SGPS, may have an important impact on multiple medical and psychosocial domains including morbidity, mortality, and quality of life (Sperling, 2004). Though the benefits of alleviating seizure severity may be difficult to assess in brief, timelimited studies, such treatment effects may decrease the frequency of accidents, injury, and death, lessen direct and indirect healthcare costs, and improve both cognitive performance and employment status (Baker, 2002; Cockerell et al., 1994; Gilliam et al., 2005; Hamer et al., 2006; Lhatoo and Sander, 2005; Strzelczyk et al., 2012). An AED that reduces SGPS would be clinically beneficial, particularly as the presence of poorly controlled primary or secondarily generalized tonic-clonic seizures is the main predictor of SUDEP (Duncan and Brodie, 2011; Hesdorffer et al., 2011; Surges et al., 2010; Tomson et al., 2008). Despite the fact that the lacosamide pivotal trials were powered to detect the effect of lacosamide on combined partial seizures rather than by focal seizure subtype, the results of these exploratory analyses revealed consistent reductions in CPS and SGPS frequency with adjunctive lacosamide. Reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS by effective treatment.
Conflicts of interest statement Dr. M. Sperling has received research support from UCB Pharma, Lundbeck, Eisai, SK Life Sciences, Sunovion, Vertex, Visualise, and Medtronics, and consulted for Acorda Therapeutics, UCB Pharma, and electroCore. Within the last 2 years, Dr. F. Rosenow has received: consulting fees from GSK, EISAI, UCB Pharma, and Pfizer; speakers honoraria from UCB Pharma, GSK, EISAI, Desitin, and Medtronic; and, educational grants from Nihon-Kohden, UCB Pharma, Medtronics, Cyberonics, and Cerbomed. Dr. E. Faught has received consulting fees from Lundbeck, Medivation, Sunovion, UCB Pharma, and Vertex, honoraria for service on data monitoring boards from Eisai, Lundbeck, and SK Life Sciences, and research support from Cyberonics, GlaxoSmithKline, and UCB Pharma. Drs. D. Hebert and P. Doty are employees of UCB Pharma. Dr. J. Isojärvi was an employee of UCB Pharma at the time of the analyses. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Acknowledgements The studies and exploratory analysis of pooled trial data was funded by UCB Pharma. Writing support was provided
1398 by Kristen A. Andersen, Ph.D. of Prescott Medical Communications Group in Chicago, Illinois, USA. Editorial support was provided by Jonathon Gibbs of Evidence Scientific Solutions, Horsham, UK. Publication management in the form of publication coordination was provided by Jesse Fishman, PharmD, and Azita Tofighy, PhD, employees of UCB Pharma.
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