Epilepsy
Conditions
Keywords
Lacosamide, Vimpat, Epilepsy, Children, Primary Generalized Tonic Clonic seizures, Idiopathic Generalized Epilepsy, Adults
Brief summary
Evaluating efficacy & safety of lacosamide versus Placebo in a blinded fashion as add-on Therapy for Primary Generalized Tonic-clonic (PGTC) seizures in subject 4 years of age or greater with idiopathic generalized epilepsy currently taking 1 to 3 antiepileptic drugs. Maximum duration of study drug administration is 28 weeks. Eligible subjects may choose to enter the open-label extension study after completion.
Interventions
* Active Substance: Lacosamide * Pharmaceutical Form: Film-coated Tablet * Concentration: 50 mg * Route of Administration: Oral use
DRUGLasosamide Oral Solution
* Active Substance: Lacosamide * Pharmaceutical Form: Oral Solution * Concentration: 10 mg/ml * Route of Administration: Oral use
OTHERPlacebo Tablet
* Active Substance: Placebo * Pharmaceutical Form: Film-coated Tablet * Concentration: 50 mg * Route of Administration: Oral use
* Active Substance: Placebo * Pharmaceutical Form: Oral Solution * Concentration: 10 mg/ml * Route of Administration: Oral use
Sponsors
Pharmaceutical Research Associates
UCB BIOSCIENCES, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject with a confirmed diagnosis at least 24 weeks prior to Visit 1 and a disease onset prior to 30 years of age, consistent with idiopathic generalized epilepsy (IGE) experiencing primary generalized tonic-clonic (PGTC) seizures (Type IIE) that are classifiable according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures (ILAE, 1981) * Subject has \>=3 PGTC seizures during the 16-week Combined Baseline (12-week Historical Baseline plus 4-week Prospective Baseline) * If a brain magnetic resonance imaging (MRI)/computed tomography (CT) scan has been performed, there must be no evidence of any progressive abnormality or any lesion likely to be associated with partial-onset seizures * Subject has been maintained on a stable dose regimen of 1 to 2 non-benzodiazepine marketed antiepileptic drugs (AEDs) with no benzodiazepine AEDs OR 1 benzodiazepine marketed AED with 1 to 2 non benzodiazepine marketed AEDs for at least 28 days prior to Visit 1 with or without additional concurrent stable vagus nerve stimulation (VNS) * Subjects are required to have had an electroencephalogram (EEG) report consistent with idiopathic generalized epilepsy (eg, generalized 3Hz epileptiform discharges and a normal EEG background) confirmed by a Central Reviewer
Exclusion criteria
* Subject is receiving any investigational drugs or using any experimental devices in addition to Lacosamide (LCM) * Subject meets the withdrawal criteria for SP0982 or is experiencing an ongoing serious adverse event (SAE) * Subject has an active suicidal ideation as indicated by a positive response ('Yes') to either Question 4 or Question 5 of the 'Since Last Visit' version of the Columbia-Suicide Severity Rating Scale (C-SSRS) * Subject has \>=2x upper limit of normal (ULN) of any of the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or \>ULN total bilirubin (\>=1.5xULN total bilirubin if known Gilbert's syndrome). If subject has elevations only in total bilirubin that are \>ULN and \<1.5xULN, fractionate bilirubin to identify possible undiagnosed Gilbert's syndrome (ie, direct bilirubin \<35%) For randomized subjects with a Baseline result \>ULN for ALT, AST, ALP, or total bilirubin, a Baseline diagnosis and/or the cause of any clinically meaningful elevation must be understood and recorded in the electronic case report form (eCRF). If subject has \>ULN ALT, AST, or ALP that does not meet the exclusion limit at screening, repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically relevant increase. In case of a clinically relevant increase, inclusion of the subject must be discussed with the Medical Monitor. Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated once for confirmation. This includes re-screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to the Second Primary Generalized Tonic Clonic (PGTC) Seizure During the 24-week Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24) | The primary efficacy variable was the time to the second primary generalized tonic clonic seizure (PGTCS) during the 24-week Treatment Period. Relative difference between groups (Lacosamide vs Placebo) was expressed as Hazard Ratio. The indicated measured values are the observed number of events of second PGTCS in the treatment period which form the basis of the statistical analysis of the time to event analysis. The hazard ratio compares 2 treatment groups for the times to a specified number of events (125) for the combined treatment groups, and so both the number of events and the times until those events pertain to the computation of the hazard ratio. A Hazard Ratio below 1 indicates time to second PGTCS was improved for LCM compared to Placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Seizure Freedom for Primary Generalized Tonic Clonic (PGTC) Seizures During the 24-week Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24) | A seizure-free day from primary generalized tonic clonic seizures (PGTCS) was defined as a day where no PGTCS were reported in the seizure diary and PGTCS were assessed, which was estimated using Kaplan-Meier (KM) methods. |
| Time to the First Primary Generalized Tonic Clonic (PGTC) Seizure During the Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24) | The secondary efficacy variable was the time to the first primary generalized tonic clonic seizure (PGTCS) during the 24-week Treatment Period. Relative difference between groups (Lacosamide vs Placebo) was expressed as Hazard Ratio. The indicated measured values are the observed number of events of first PGTCS in the treatment period which form the basis of the statistical analysis of the time to event analysis. The hazard ratio compares 2 treatment groups for the times to the number of events for the combined treatment groups, and so both the number of events and the times until those events pertain to the computation of the hazard ratio. A Hazard Ratio below 1 indicates time to second PGTCS was improved for LCM compared to Placebo. |
| Percentage of Participants With at Least One Adverse Event (AE) as Reported Spontaneously by the Subject and/or Caregiver or Observed by the Investigator | From Visit 1 (Week -4) to End of Study Period (up to Week 36) | An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product (IMP), whether or not related to the IMP. |
| Plasma Concentrations of Lacosamide | During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24) | Lacosamide plasma concentration was expressed in micrograms per milliliter (μg/mL). Means and standard deviation (SD) were only calculated if at least 2/3 of the concentrations were quantified at the respective timepoint. Values Below Limit of Quantification (BLQ) were replaced by value of 0 in calculations of means and SDs. |
Countries
Australia, Belgium, Brazil, Bulgaria, China, Czechia, France, Germany, Hungary, Israel, Italy, Japan, Mexico, Poland, Portugal, Romania, Russia, Slovakia, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
The study started to enroll patients in April 2015 and concluded in May 2019.
Pre-assignment details
Completed study was defined as meeting any exit criteria or completing the 24-week Treatment Period with \< 2 PGTCS. After Treatment Period participants enrolled either in a 4-week Transition Period (entered EP0012) or up to a 4-week Taper Period and a 30-day Safety Follow-up Period (did not enter EP0012). Participant Flow refers to the Safety Set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants \>= 50 kg.
Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants \< 30 kg).
Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to \< 50 kg). | 121 |
| Lacosamide Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (\>=) 50 kilograms (kg).
Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (\<) 30 kg).
Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to \< 50 kg). | 121 |
| Total Title | 242 |
| Total | 484 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 10 |
| Overall Study | Did not satisfy extension conditions | 0 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Sponsor request | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Lacosamide | Total Title |
|---|---|---|---|
| Age, Categorical <=18 years | 27 Participants | 28 Participants | 55 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 93 Participants | 92 Participants | 185 Participants |
| Age, Continuous | 27.64 years STANDARD_DEVIATION 12.45 | 27.82 years STANDARD_DEVIATION 13.13 | 27.73 years STANDARD_DEVIATION 12.77 |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 25 Participants | 18 Participants | 43 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Other/Mixed | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 89 Participants | 97 Participants | 186 Participants |
| Sex: Female, Male Female | 76 Participants | 66 Participants | 142 Participants |
| Sex: Female, Male Male | 45 Participants | 55 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 121 | 0 / 121 | 0 / 108 | 0 / 101 | 0 / 7 | 0 / 9 | 0 / 10 | 0 / 11 |
| other Total, other adverse events | 41 / 121 | 60 / 121 | 27 / 108 | 5 / 101 | 3 / 7 | 2 / 9 | 0 / 10 | 0 / 11 |
| serious Total, serious adverse events | 4 / 121 | 8 / 121 | 0 / 108 | 3 / 101 | 0 / 7 | 0 / 9 | 1 / 10 | 1 / 11 |
Outcome results
Primary
Time to the Second Primary Generalized Tonic Clonic (PGTC) Seizure During the 24-week Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24)
The primary efficacy variable was the time to the second primary generalized tonic clonic seizure (PGTCS) during the 24-week Treatment Period. Relative difference between groups (Lacosamide vs Placebo) was expressed as Hazard Ratio. The indicated measured values are the observed number of events of second PGTCS in the treatment period which form the basis of the statistical analysis of the time to event analysis. The hazard ratio compares 2 treatment groups for the times to a specified number of events (125) for the combined treatment groups, and so both the number of events and the times until those events pertain to the computation of the hazard ratio. A Hazard Ratio below 1 indicates time to second PGTCS was improved for LCM compared to Placebo.
Time frame: During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
Population: The Full Analysis Set (FAS) was a subset of the Safety Set (SS) that consisted of all study participants with at least 1 seizure diary assessment during the Treatment Period.~1 patient from the Lacosamide (FAS) group was randomized after the 125th event and did not appear in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | Time to the Second Primary Generalized Tonic Clonic (PGTC) Seizure During the 24-week Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | 76 events |
| Lacosamide (FAS) | Time to the Second Primary Generalized Tonic Clonic (PGTC) Seizure During the 24-week Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | 49 events |
Comparison: Comparison of LCM versus Placebo was based on a Cox proportional hazards regression model with an effect for treatment, stratifying for the following combinations of study participants' Baseline PGTCS frequency and Development from interactive response technology (IRT) (\<= 2 per 28 days in the Combined Baseline Period and Pediatric, \<= 2 per 28 days in the Combined Baseline Period and Adult, and \> 2 per 28 days in the Combined Baseline Period). The reference group was Placebo.p-value: <0.00195% CI: [0.377, 0.774]Regression, Cox
Secondary
Percentage of Participants With at Least One Adverse Event (AE) as Reported Spontaneously by the Subject and/or Caregiver or Observed by the Investigator
An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product (IMP), whether or not related to the IMP.
Time frame: From Visit 1 (Week -4) to End of Study Period (up to Week 36)
Population: The Safety Set (SS) was a subset of the Randomized Set (RS) and consisted of all study participants who had been treated with at least 1 dose of study medication, either LCM or Placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | Percentage of Participants With at Least One Adverse Event (AE) as Reported Spontaneously by the Subject and/or Caregiver or Observed by the Investigator | 81.8 percentage of participants |
| Lacosamide (FAS) | Percentage of Participants With at Least One Adverse Event (AE) as Reported Spontaneously by the Subject and/or Caregiver or Observed by the Investigator | 82.6 percentage of participants |
Secondary
Percentage of Participants With Seizure Freedom for Primary Generalized Tonic Clonic (PGTC) Seizures During the 24-week Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24)
A seizure-free day from primary generalized tonic clonic seizures (PGTCS) was defined as a day where no PGTCS were reported in the seizure diary and PGTCS were assessed, which was estimated using Kaplan-Meier (KM) methods.
Time frame: During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
Population: The Full Analysis Set (FAS) was a subset of the Safety Set (SS) that consisted of all study participants with at least 1 seizure diary assessment during the Treatment Period.~1 patient from the Lacosamide (FAS) group was randomized after the 125th event and did not appear in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | Percentage of Participants With Seizure Freedom for Primary Generalized Tonic Clonic (PGTC) Seizures During the 24-week Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | 17.3 percentage of participants |
| Lacosamide (FAS) | Percentage of Participants With Seizure Freedom for Primary Generalized Tonic Clonic (PGTC) Seizures During the 24-week Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | 31.0 percentage of participants |
Comparison: The key secondary efficacy variable was evaluated using an extended Mantel-Haenszel testing procedure. Baseline PGTCS Frequency from Combined Baseline and development (age from interactive response technology (IRT)) were calculated from IRT.p-value: =0.01195% CI: [3.2, 25.1]Mantel Haenszel
Secondary
Plasma Concentrations of Lacosamide
Lacosamide plasma concentration was expressed in micrograms per milliliter (μg/mL). Means and standard deviation (SD) were only calculated if at least 2/3 of the concentrations were quantified at the respective timepoint. Values Below Limit of Quantification (BLQ) were replaced by value of 0 in calculations of means and SDs.
Time frame: During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
Population: The Safety Set (SS) was a subset of the Randomized Set (RS) and consisted of all study participants who had been treated with at least 1 dose of study medication, either LCM or Placebo.~Data not collected from participants in Placebo (SS) Arm/Group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lacosamide (FAS) | Plasma Concentrations of Lacosamide | Visit 5, Week 6 (Titration) | 8.610961 ug/mL | Standard Deviation 3.705438 |
| Lacosamide (FAS) | Plasma Concentrations of Lacosamide | Visit 10, Week 24 (Maintenance) | 8.074427 ug/mL | Standard Deviation 3.948749 |
| Lacosamide (FAS) | Plasma Concentrations of Lacosamide | Early Termination Visit | 8.138085 ug/mL | Standard Deviation 4.913627 |
Secondary
Time to the First Primary Generalized Tonic Clonic (PGTC) Seizure During the Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24)
The secondary efficacy variable was the time to the first primary generalized tonic clonic seizure (PGTCS) during the 24-week Treatment Period. Relative difference between groups (Lacosamide vs Placebo) was expressed as Hazard Ratio. The indicated measured values are the observed number of events of first PGTCS in the treatment period which form the basis of the statistical analysis of the time to event analysis. The hazard ratio compares 2 treatment groups for the times to the number of events for the combined treatment groups, and so both the number of events and the times until those events pertain to the computation of the hazard ratio. A Hazard Ratio below 1 indicates time to second PGTCS was improved for LCM compared to Placebo.
Time frame: During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
Population: The Full Analysis Set (FAS) was a subset of the Safety Set (SS) that consisted of all study participants with at least 1 seizure diary assessment during the Treatment Period.~1 patient from the Lacosamide (FAS) group was randomized after the 125th event and did not appear in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | Time to the First Primary Generalized Tonic Clonic (PGTC) Seizure During the Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | 97 events |
| Lacosamide (FAS) | Time to the First Primary Generalized Tonic Clonic (PGTC) Seizure During the Treatment Period From Visit 2 (Week 0) to Visit 10 (Week 24) | 79 events |
Comparison: Comparison of LCM versus Placebo was based on a Cox proportional hazards regression model with an effect for treatment, stratifying for the following combinations of study participants' Baseline PGTCS frequency and Development from interactive response technology (IRT) (\<= 2 per 28 days in the Combined Baseline Period and Pediatric, \<= 2 per 28 days in the Combined Baseline Period and Adult, and \> 2 per 28 days in the Combined Baseline Period). The reference group was Placebo.p-value: =0.01295% CI: [0.507, 0.921]Regression, Cox