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Lacosamide as Adjunct for Generalized Seizures

Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials

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Year of Publication: 2015

Authors: Victor Biton, Antonio Gil-Nagel, Jouko Isojarvi, ..., Nathan B. Fountain

Journal: Epilepsy & Behavior

Citation: Epilepsy Behav. 2015;52:119-127

Link: http://dx.doi.org/10.1016/j.yebeh.2015.09.006

PDF: https://www.epilepsybehavior.com/action/...%2815%2900521-1

Clinical Question

What is the safety and tolerability profile of adjunctive lacosamide (200-600 mg/day) in adults with partial-onset seizures based on pooled data from three pivotal trials?

Bottom Line

Adjunctive lacosamide was generally well tolerated in adults with partial-onset seizures. Most TEAEs were mild or moderate in intensity and occurred predominantly during the titration phase. Common drug-associated TEAEs were dose-related and included dizziness, nausea, and diplopia. The approved dose range (200-400 mg/day) showed better tolerability than 600 mg/day, with cognition-related TEAEs similar to placebo.

        Major Points
        Pooled safety analysis of 1308 patients from three phase II/III trials (SP667, SP754, SP755)
944 patients received lacosamide (200mg n=270; 400mg n=471; 600mg n=203) and 364 received placebo
Most common drug-associated TEAEs: dizziness (30.6% vs 8.2%), nausea (11.4% vs 4.4%), diplopia (10.5% vs 1.9%)
TEAEs were dose-related: any TEAE in 69.6% (200mg), 82.2% (400mg), 93.6% (600mg) vs 64.6% placebo
Most TEAEs were mild (32.2%) or moderate (38.3%); severe TEAEs in 10.4% lacosamide vs 4.7% placebo
TEAE incidence was notably lower during maintenance phase than titration phase
Discontinuation due to TEAEs: 8.1% (200mg), 17.2% (400mg), 28.6% (600mg) vs 4.9% placebo
Cognition-related TEAEs at approved doses (200-400mg combined): 6.1% vs 4.7% placebo (OR 1.3, 95% CI 0.7-2.4)
No individual serious TEAE occurred in ≥1% of lacosamide-treated patients
80.6% of patients enrolled in subsequent open-label extension trials

      

Design

Study Type: Pooled analysis of three randomized, double-blind, placebo-controlled trials (SP667, SP754, SP755)

Randomization: 1

Blinding: Double-blind in all three component trials

Enrollment Period: SP667 (Europe + US), SP754 (US), SP755 (Europe + Australia)

Follow-up Duration: 8-week baseline + 4-6 week titration + 12-week maintenance + 2-3 week taper

Countries: United States, Europe, Australia

Sample Size: 1308

Analysis: A priori protocol-defined and post hoc safety analyses on pooled data; descriptive statistics; logistic regression for cognition-related TEAEs with adjustment for trial; TEAEs coded using MedDRA version 9.1

Inclusion Criteria

Age 16-70 years (18-65 in SP667)
Diagnosis of focal epilepsy
Partial-onset seizures (with or without secondary generalization) for ≥2 years
≥2 previous AEDs (concurrently or sequentially) that failed to control seizures
Average ≥4 POS per 28 days during 8-week baseline
Seizure-free periods lasting no longer than 21 days
Stable dosing regimen of 1-3 concomitant AEDs (≤2 in SP667) for ≥4 weeks
With or without vagus nerve stimulation

Exclusion Criteria

Not detailed in pooled analysis paper

Baseline Characteristics

Placebo:

N: 364
Age - mean ± SD, years: 38.5 ± 11.25
Female: 177 (48.6%)
Time since diagnosis - mean ± SD, years: 23.3 ± 12.56
Lifetime AEDs 1-3: 80 (22.0%)
Lifetime AEDs 4-6: 121 (33.2%)
Lifetime AEDs ≥7: 160 (44.0%)
1 concomitant AED: 62 (17.0%)
2 concomitant AEDs: 214 (58.8%)
3 concomitant AEDs: 88 (24.2%)
Carbamazepine use: 129 (35.4%)
Lamotrigine use: 117 (32.1%)
Levetiracetam use: 103 (28.3%)
Valproate use: 95 (26.1%)
Topiramate use: 83 (22.8%)
Median baseline seizures per 28 days: 11.0

Lacosamide 200mg:

N: 270
Age - mean ± SD, years: 38.1 ± 11.78
Female: 134 (49.6%)
Time since diagnosis - mean ± SD, years: 23.7 ± 12.56
Lifetime AEDs 1-3: 62 (23.0%)
Lifetime AEDs 4-6: 84 (31.1%)
Lifetime AEDs ≥7: 120 (44.4%)
1 concomitant AED: 34 (12.6%)
2 concomitant AEDs: 168 (62.2%)
3 concomitant AEDs: 68 (25.2%)
Carbamazepine use: 115 (42.6%)
Lamotrigine use: 70 (25.9%)
Levetiracetam use: 70 (25.9%)
Valproate use: 74 (27.4%)
Topiramate use: 70 (25.9%)
Median baseline seizures per 28 days: 12.2

Lacosamide 400mg:

N: 471
Age - mean ± SD, years: 39.2 ± 12.44
Female: 245 (52.0%)
Time since diagnosis - mean ± SD, years: 24.0 ± 13.14
Lifetime AEDs 1-3: 112 (23.8%)
Lifetime AEDs 4-6: 151 (32.1%)
Lifetime AEDs ≥7: 205 (43.5%)
1 concomitant AED: 78 (16.6%)
2 concomitant AEDs: 281 (59.7%)
3 concomitant AEDs: 112 (23.8%)
Carbamazepine use: 150 (31.8%)
Lamotrigine use: 159 (33.8%)
Levetiracetam use: 147 (31.2%)
Valproate use: 99 (21.0%)
Topiramate use: 106 (22.5%)
Median baseline seizures per 28 days: 11.0

Lacosamide 600mg:

N: 203
Age - mean ± SD, years: 38.1 ± 11.18
Female: 111 (54.7%)
Time since diagnosis - mean ± SD, years: 23.5 ± 12.97
Lifetime AEDs 1-3: 32 (15.8%)
Lifetime AEDs 4-6: 68 (33.5%)
Lifetime AEDs ≥7: 102 (50.2%)
1 concomitant AED: 30 (14.8%)
2 concomitant AEDs: 151 (74.4%)
3 concomitant AEDs: 22 (10.8%)
Carbamazepine use: 69 (34.0%)
Lamotrigine use: 62 (30.5%)
Levetiracetam use: 61 (30.0%)
Valproate use: 40 (19.7%)
Topiramate use: 32 (15.8%)
Median baseline seizures per 28 days: 13.5

Arms

Field	Control	Lacosamide 200 mg/day	Lacosamide 400 mg/day	Lacosamide 600 mg/day
Intervention	Placebo twice daily in equally divided doses	Lacosamide 200 mg/day (100 mg BID) after titration; one 100 mg/day back-titration allowed for intolerable AEs	Lacosamide 400 mg/day (200 mg BID) after titration; one 100 mg/day back-titration allowed for intolerable AEs	Lacosamide 600 mg/day (300 mg BID) after titration; one 100 mg/day back-titration allowed for intolerable AEs
Duration	4-6 week titration + 12-week maintenance	4-6 week titration + 12-week maintenance	4-6 week titration + 12-week maintenance	4-6 week titration + 12-week maintenance

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR
Treatment-emergent adverse events (TEAEs) during treatment phase (titration + maintenance), including overall TEAEs, serious TEAEs, and discontinuations due to TEAEs	Primary	Any TEAE: 64.6%; Drug-related TEAE: 38.7%; Discontinuation due to TEAE: 4.9%	Any TEAE: 69.6% (200mg), 82.2% (400mg), 93.6% (600mg); Drug-related: 44.1%, 62.8%, 79.8%; Discontinuation: 8.1%, 17.2%, 28.6%
Trial completion rate	Secondary	317/364 (87.1%)	81.9% (200mg); 77.1% (400mg); 62.1% (600mg)
Enrollment in open-label extension	Secondary	Included in total	1054/1308 (80.6%) total enrolled in OLE
TEAE intensity - Mild	Secondary	38.5%	32.2% (all lacosamide)
TEAE intensity - Moderate	Secondary	21.4%	38.3% (all lacosamide)
TEAE intensity - Severe	Secondary	4.7%	7.0% (200mg); 9.1% (400mg); 17.7% (600mg); 10.4% overall
Any TEAE during titration phase	Secondary	53.3%	51.1% (200mg); 69.9% (400mg); 87.7% (600mg); 68.3% overall
Any TEAE during maintenance phase	Secondary	44.5% (150/337)	54.9% (200mg); 62.3% (400mg); 63.4% (600mg); 60.2% overall
Serious TEAEs	Secondary	14 (3.8%)	7.8% (200mg); 7.2% (400mg); 3.0% (600mg); 6.5% overall
Cognition-related TEAEs (post hoc)	Secondary	17 (4.7%)	1.9% (200mg); 8.5% (400mg); 13.8% (600mg); 7.7% overall	OR 1.3 (95% CI 0.7-2.4) for 200-400mg combined vs placebo
Cognition-related TEAEs at approved dose range (200-400mg)	Secondary	4.7%	6.1%	OR 1.3 (95% CI 0.7-2.4)
Dizziness	Adverse	30 (8.2%)	43 (15.9%) 200mg; 139 (29.5%) 400mg; 107 (52.7%) 600mg; 289 (30.6%) all
Nausea	Adverse	16 (4.4%)	20 (7.4%) 200mg; 53 (11.3%) 400mg; 35 (17.2%) 600mg; 108 (11.4%) all
Diplopia	Adverse	7 (1.9%)	17 (6.3%) 200mg; 49 (10.4%) 400mg; 33 (16.3%) 600mg; 99 (10.5%) all
Headache	Adverse	32 (8.8%)	120 (12.7%) all lacosamide
Vomiting	Adverse	9 (2.5%)	16 (5.9%) 200mg; 40 (8.5%) 400mg; 32 (15.8%) 600mg; 88 (9.3%) all
Fatigue	Adverse	21 (5.8%)	19 (7.0%) 200mg; 34 (7.2%) 400mg; 30 (14.8%) 600mg; 83 (8.8%) all
Vision blurred	Adverse	9 (2.5%)	6 (2.2%) 200mg; 40 (8.5%) 400mg; 33 (16.3%) 600mg; 79 (8.4%) all
Ataxia (coordination abnormal)	Adverse	6 (1.6%)	11 (4.1%) 200mg; 34 (7.2%) 400mg; 31 (15.3%) 600mg; 76 (8.1%) all
Tremor	Adverse	15 (4.1%)	10 (3.7%) 200mg; 29 (6.2%) 400mg; 24 (11.8%) 600mg; 63 (6.7%) all
Nystagmus	Adverse	14 (3.8%)	6 (2.2%) 200mg; 21 (4.5%) 400mg; 21 (10.3%) 600mg; 48 (5.1%) all
Memory impairment	Adverse	6 (1.6%)	3 (1.1%) 200mg; 7 (1.5%) 400mg; 12 (5.9%) 600mg; 22 (2.3%) all
Rash (all types)	Adverse	11 (3.0%)	4 (1.5%) 200mg; 16 (3.4%) 400mg; 7 (3.4%) 600mg; 27 (2.9%) all
Depression	Adverse	2 (0.5%)	6 (2.2%) 200mg; 11 (2.3%) 400mg; 3 (1.5%) 600mg; 20 (2.1%) all
Seizure-related TEAEs	Adverse	19 (5.2%)	46 (4.9%) all lacosamide
Convulsion (TEAE)	Adverse	13 (3.6%)	37 (3.9%) all lacosamide
First degree AV block	Adverse	0 (0%)	2 (200mg); 1 (400mg); 1 (600mg); 4 total
Death	Adverse	0 (0%)	1 (suicide, 200mg group)
Discontinuation due to dizziness	Adverse	2 (0.5%)	1 (0.4%) 200mg; 20 (4.2%) 400mg; 35 (17.2%) 600mg; 56 (5.9%) all
Discontinuation due to ataxia	Adverse	0 (0%)	1 (0.4%) 200mg; 6 (1.3%) 400mg; 11 (5.4%) 600mg; 18 (1.9%) all

Subgroup Analysis

Discontinuations due to TEAEs by concomitant AED (lacosamide all doses vs placebo): carbamazepine 15.3% vs 3.9%, lamotrigine 19.2% vs 4.3%, levetiracetam 10.1% vs 3.9%, valproate 15.5% vs 1.1%, topiramate 11.5% vs 3.6%. Results suggest nervous system TEAEs occurred more frequently with concomitant sodium channel blockers. Cognition-related TEAEs by dose: OR 0.4 (200mg), OR 1.7 (400mg), OR 2.8 (600mg) vs placebo. PR interval increase was dose-related (placebo-adjusted): 1.5ms (200mg), 3.1ms (400mg), 4.5ms (600mg).

Criticisms

Pooled analysis rather than prospective trial design
Forced titration protocol may not reflect real-world clinical practice where flexible dosing is used
Post hoc nature of cognition-related TEAE analysis limits conclusions
Concomitant AED subgroup analysis limited by unbalanced sample sizes and non-mutually exclusive groups (84% on ≥2 AEDs)
600 mg/day dose not within approved dose range but included in analysis
Different titration schedules across the three component trials (4-6 weeks)
SP667 limited to ≤2 concomitant AEDs while SP754/SP755 allowed up to 3
Safety set analysis includes patients who received at least one dose, potentially underestimating tolerability issues in those who discontinued early
Three UCB Pharma employees among authors
Relatively short maintenance phase (12 weeks) for long-term safety assessment

Funding

UCB Biosciences Inc., Raleigh, NC, USA

Based on: Lacosamide as Adjunct for Generalized Seizures (Epilepsy & Behavior, 2015)