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KOMET

Keppra vs Older Monotherapy in Epilepsy Trial: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy

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Year of Publication: 2013

Authors: Eugen Trinka, Anthony G Marson, Wim Van Paesschen, ..., for the KOMET Study Group

Journal: Journal of Neurology, Neurosurgery & Psychiatry

Citation: J Neurol Neurosurg Psychiatry 2013;84:1138–1147

PDF: https://www.researchgate.net/profile/Eug...as-monother.pdf

Clinical Question

Is levetiracetam superior to standard antiepileptic drugs (extended-release sodium valproate or controlled-release carbamazepine) as first-line monotherapy in patients with newly diagnosed epilepsy?

Bottom Line

Levetiracetam monotherapy was not superior to standard AEDs (valproate or carbamazepine) for time to treatment withdrawal in patients with newly diagnosed focal or generalised seizures. Standard AEDs showed a modest advantage for seizure freedom, while LEV may offer better tolerability, particularly compared to carbamazepine.

Major Points

  • LEV was not superior to standard AEDs for the primary outcome of time to treatment withdrawal (HR 0.90, 95% CI 0.74-1.08)
  • Standard AEDs showed significantly longer time to first seizure compared to LEV (HR 1.20, 95% CI 1.03-1.39, p=0.022)
  • 12-month seizure freedom rates were 53.9% for LEV vs 59.9% for standard AEDs
  • In the VPA stratum, time to treatment withdrawal was similar between LEV and VPA-ER (HR 1.02, 95% CI 0.74-1.41)
  • In the CBZ stratum, LEV showed a trend toward better retention vs CBZ-CR (HR 0.84, 95% CI 0.66-1.07)
  • Discontinuation due to adverse events was lower with LEV (8.3%) than standard AEDs (13.1%)
  • LEV may be a viable first-line option for women of childbearing age given lower teratogenicity compared to valproate
  • 75% of patients in the ITT population remained on their randomized drug at 12 months

Design

Study Type: Multicentre, unblinded, randomised, controlled, superiority trial with two-parallel-group, stratified design

Randomization: 1

Blinding: Unblinded (open-label). Treatment allocation was concealed using an Interactive Voice Response System via telephone

Enrollment Period: February 2005 to October 2007

Follow-up Duration: 52 weeks

Centers: 269

Countries: Australia, Austria, Belgium, Czech Republic, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, UK, and 11 other European countries

Sample Size: 1688

Analysis: Intention-to-treat analysis. Kaplan-Meier survival curves for time to event. Cox proportional hazards regression model for treatment effect (HR with 95% CI). Log-rank test for sample size calculation. Two-sided α=0.05. Power 90%.

Inclusion Criteria

  • Age ≥16 years
  • Two or more unprovoked seizures in the previous 2 years
  • At least one seizure during the previous 6 months
  • Seizures classified according to ILAE classification
  • Written informed consent

Exclusion Criteria

  • Previous treatment with LEV, VPA, or CBZ for any indication
  • Treatment for epilepsy with any other AED in the last 6 months
  • Acute seizure treatment >2 weeks duration or stopped <1 week before screening

Baseline Characteristics

LEV (N=841):

  • Age, years, mean±SD: 40.6±17.8
  • Age ≥16 to <65, n (%): 726 (86.3%)
  • Age ≥65, n (%): 115 (13.7%)
  • Men, n (%): 466 (55.4%)
  • Women, n (%): 375 (44.6%)
  • Number of seizures in last 2 years, median (Q1-Q3): 3 (2-7)
  • Epilepsy duration, years, median (Q1-Q3): 0.86 (0.31-2.94)
  • Focal seizures, n (%): 543 (64.6%)
  • Primary generalised seizures, n (%): 297 (35.3%)
  • Unclassified only, n (%): 18 (2.1%)

Standard AEDs (N=847):

  • Age, years, mean±SD: 40.9±17.8
  • Age ≥16 to <65, n (%): 734 (86.7%)
  • Age ≥65, n (%): 113 (13.3%)
  • Men, n (%): 476 (56.2%)
  • Women, n (%): 371 (43.8%)
  • Number of seizures in last 2 years, median (Q1-Q3): 3 (2-8)
  • Epilepsy duration, years, median (Q1-Q3): 0.99 (0.35-2.74)
  • Focal seizures, n (%): 549 (64.8%)
  • Primary generalised seizures, n (%): 290 (34.2%)
  • Unclassified only, n (%): 18 (2.1%)

LEV VPA stratum (N=349):

  • Age, years, mean±SD: 35.9±17.8
  • Men, n (%): 191 (54.7%)
  • Focal seizures, n (%): 109 (31.2%)
  • Primary generalised seizures, n (%): 235 (67.3%)

VPA-ER (N=347):

  • Age, years, mean±SD: 38.2±17.9
  • Men, n (%): 202 (58.2%)
  • Focal seizures, n (%): 101 (29.1%)
  • Primary generalised seizures, n (%): 242 (69.7%)

LEV CBZ stratum (N=492):

  • Age, years, mean±SD: 44.0±17.0
  • Men, n (%): 275 (55.9%)
  • Focal seizures, n (%): 434 (88.2%)
  • Primary generalised seizures, n (%): 62 (12.6%)

CBZ-CR (N=500):

  • Age, years, mean±SD: 42.7±17.5
  • Men, n (%): 274 (54.8%)
  • Focal seizures, n (%): 448 (89.6%)
  • Primary generalised seizures, n (%): 48 (9.6%)

Arms

FieldLevetiracetam (LEV)ControlControl
InterventionLEV starting dose 500 mg/day, up-titrated over 2 weeks to initial target dose of 1000 mg/day, administered twice daily as equal doses. Maximum dose 3000 mg/day if seizures occurred. Median daily dose: 987 mg/day (range 250-2807)VPA-ER starting dose 500 mg/day, up-titrated over 2 weeks to initial target dose of 1000 mg/day, administered twice daily as equal doses. Maximum dose 2000 mg/day. Median daily dose: 987 mg/day (range 500-2263)CBZ-CR starting dose 200 mg/day, up-titrated over 2 weeks to initial target dose of 600 mg/day, administered twice daily as equal doses. Maximum dose 1600 mg/day. Median daily dose: 588 mg/day (range 180-1422)
Duration52 weeks52 weeks52 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Time to treatment withdrawal from study medication calculated from randomisation to the day after the last intake of study medication (LEV vs standard AEDs combined)Primary219 events (25.9%); 12-month withdrawal rate 25.9%200 events (23.8%); 12-month withdrawal rate 23.9%0.90.258
Time to treatment withdrawal: LEV vs VPA-ERSecondary12-month withdrawal rate 21.6% (95% CI 17.7-26.4)12-month withdrawal rate 22.0% (95% CI 18.0-26.7)1.020.882
Time to treatment withdrawal: LEV vs CBZ-CRSecondary12-month withdrawal rate 28.8% (95% CI 25.1-33.0)12-month withdrawal rate 25.2% (95% CI 21.6-29.3)0.840.161
Time to first seizure: LEV vs standard AEDsSecondary305 events (36.0%); 12-month seizure freedom 59.9%355 events (42.2%); 12-month seizure freedom 53.9%1.20.022
Time to first seizure: LEV vs VPA-ERSecondary12-month seizure freedom 64.5% (95% CI 58.9-69.5)12-month seizure freedom 58.7% (95% CI 53.1-63.9)1.190.167
Time to first seizure: LEV vs CBZ-CRSecondary12-month seizure freedom 56.7% (95% CI 51.8-61.2)12-month seizure freedom 50.5% (95% CI 45.8-55.1)1.20.061
Time to first seizure: LEV vs CBZ-CR (focal seizures only)Secondary12-month seizure freedom 56.2% (95% CI 51.0-61.0)12-month seizure freedom 48.1% (95% CI 42.9-53.1)1.24<0.05
≥1 treatment-emergent AE (LEV vs Standard AEDs)Adverse574 (68.3%)587 (70.3%)
≥1 treatment-emergent AE (VPA stratum: LEV vs VPA-ER)Adverse212 (62.0%)228 (66.1%)
≥1 treatment-emergent AE (CBZ stratum: LEV vs CBZ-CR)Adverse362 (72.5%)359 (73.4%)
Drug-related AEs (LEV vs Standard AEDs)Adverse418 (49.7%)381 (45.6%)
Discontinuation due to AEs (LEV vs Standard AEDs)Adverse110 (13.1%)69 (8.3%)
Discontinuation due to AEs (VPA stratum: LEV vs VPA-ER)Adverse16 (4.7%)21 (6.1%)
Discontinuation due to AEs (CBZ stratum: LEV vs CBZ-CR)Adverse94 (18.8%)48 (9.8%)
Serious AEs (LEV vs Standard AEDs)Adverse61 (7.3%)106 (12.7%)
Severe AEs (LEV vs Standard AEDs)Adverse92 (10.9%)130 (15.6%)
Headache (LEV vs Standard AEDs)Adverse170 (20.2%)161 (19.3%)
Fatigue (LEV vs Standard AEDs)Adverse134 (15.9%)120 (14.4%)
Dizziness (LEV vs Standard AEDs)Adverse70 (8.3%)68 (8.1%)
Somnolence (LEV vs Standard AEDs)Adverse48 (5.7%)68 (8.1%)
Weight increased (LEV vs Standard AEDs)Adverse98 (11.7%)47 (5.6%)
Weight increased (VPA stratum: LEV vs VPA-ER)Adverse65 (19.0%)21 (6.1%)
Depression (LEV vs Standard AEDs)Adverse20 (2.4%)43 (5.1%)
Tremor (VPA stratum: LEV vs VPA-ER)Adverse32 (9.4%)4 (1.2%)
Rash (CBZ stratum: LEV vs CBZ-CR)Adverse29 (5.8%)9 (1.8%)
DeathsAdverse3 (0.4%)5 (0.6%)None related to study medication

Subgroup Analysis

Post hoc subgroup analysis by seizure type: In VPA stratum, generalised seizures showed non-significant trend favoring VPA-ER for treatment withdrawal (HR 1.16, 95% CI 0.79-1.71) while focal seizures favored LEV (HR 0.73, 95% CI 0.37-1.44). In CBZ stratum, focal seizures showed similar results to overall (HR 0.84, 95% CI 0.65-1.09); generalised seizures favored LEV but with small numbers (HR 0.49, 95% CI 0.16-1.49). For time to first seizure in focal seizures (CBZ stratum), CBZ-CR was significantly better (HR 1.24, 95% CI 1.01-1.52).

Criticisms

  • Open-label (unblinded) design introduces potential for bias in outcome assessment and patient/physician behavior
  • Selection of patients at the discretion of the physician may have introduced selection bias
  • Choice of best recommended treatment (VPA vs CBZ) was not standardized according to expert recommendations
  • Neuroimaging and EEG were not mandatory before treatment selection, potentially leading to misclassification
  • Initial target dose of CBZ-CR (600 mg/day) may have been unnecessarily high, contributing to higher discontinuation rates
  • 12-month follow-up may be insufficient for long-term effectiveness assessment in epilepsy
  • Study did not reach target enrollment of 1964 patients (enrolled 1688), though still adequately powered
  • Higher incidence of serious AEs with LEV (12.7%) vs standard AEDs (7.3%) requires further investigation
  • VPA stratum included approximately 30% patients with focal seizures who may not have received optimal standard treatment
  • Trial was designed before SANAD results identified lamotrigine as preferred for focal epilepsy

Funding

UCB Pharma (manufacturer of levetiracetam/Keppra). UCB Pharma was responsible for design and conduct of the study, and collection, management, analysis and interpretation of data. Medical writing assistance funded by UCB Pharma.

Based on: KOMET (Journal of Neurology, Neurosurgery & Psychiatry, 2013)

Authors: Eugen Trinka, Anthony G Marson, Wim Van Paesschen, ..., for the KOMET Study Group

Citation: J Neurol Neurosurg Psychiatry 2013;84:1138–1147

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