Epilepsy, Monotherapy
Conditions
Keywords
Lacosamide, Vimpat®, Epilepsy, Monotherapy, Velocity
Brief summary
Compare efficacy and safety of Lacosamide (LCM) to Carbamazepine Controlled-Release (CBZ-CR) as monotherapy in newly or recently newly diagnosed subjects with a primary efficacy endpoint of 6-month seizure freedom. Noninferiority design to show a similar risk/benefit balance between Lacosamide (LCM) and Carbamazepine-CR (CBZ-CR).
Interventions
DRUGLacosamide
Lacosamide: * Strengths: 50 mg / 100 mg * Form: tablets * Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose * Duration: up to 118 weeks
DRUGCarbamazepine-Controlled Release
Carbamazepine-CR: * Strengths: 200 mg * Form: tablets * Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose * Duration: up to 118 weeks
Sponsors
Eden Sarl
UCB BIOSCIENCES GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject able to comply with study requirements * Subject is 16 years and older (female; male). Minors will be included in countries only if legally permitted * Subject has newly or recently diagnosed Epilepsy experiencing partial onset seizures (POS) or generalized tonic-clonic seizures with at least 2 unprovoked seizures separated by 48 hours in the 12 months preceding Visit 1 out of which at least 1 seizure occured 3 months preceding Visit 1 * Subject has had an Electroencephalogram (EEG) and a brain Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) exam of the brain within the past 12 months. If the EEG and brain CT scan or MRI exam were not performed prior to Visit 1, they need to be completed and results must be available prior to randomization at Visit 2
Exclusion criteria
* Subject has a history or presence of seizures of other types than partial-onset (IA, IB, IC with clear focal origin) and generalized tonic-clonic (without clear focal origin) seizures (eg, myoclonic, absence) * Subject has a history or presence of seizures occurring only in clustered patterns, defined as repeated seizures occurring over a short period of time (ie, \< 20 minutes) with or without function regained between 2 ictal events * Subject has a history, clinical, or Electroencephalogram (EEG) finding suggestive of Idiopathic Generalized Epilepsy (IGE) at randomization * Subject has current or previous diagnosis of pseudoseizures, conversion disorders, or other nonepileptic ictal events that could be confused with seizures based on expert opinion and/or EEG evidence * Subject has any medical or psychiatric condition * Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (Yes) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening * Subject has received treatment with Phenobarbital or Primidone within 28 days prior to Visit 1 * Subject is taking Benzodiazepines for a nonepilepsy indication * Subject has been treated for Epilepsy with any Antiepileptic Drug (AED) (including Benzodiazepines) in the last 6 months before Visit. However, acute and subacute seizure treatment is accepted with a maximum of 2 weeks duration and if treatment was stopped at least 3 days prior to randomization * Prior use of Felbamate or Vigabatrin is not allowed * Benzodiazepines as rescue therapy for Epilepsy may have been used as needed in this time period, but not more frequently than once per week * Subject has a medical condition that could reasonably be expected to interfere with drug absorption, distribution, metabolism, or excretion, has a history of alcohol or drug abuse within the previous 2 years * Asian ancestry and tests positive for HLA-B\*1502 allele * Asian ancestry and tests positive for HLA-A\*3101 allele
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects in the Full Analysis Set (FAS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject | 6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject | The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods. |
| Proportion of Subjects in the Per Protocol Set (PPS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject | 6 consecutive months (26 consecutive weeks) of treatment | The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods. |
| Number of Subjects With at Least One Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks) | Duration of the Treatment Phase (up to 113 weeks) | An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose. |
| Number of Subjects Who Withdraw From the Study Due to a Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks) | Duration of the Treatment Phase (up to 113 weeks) | An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose. |
| Number of Subjects With at Least One Treatment-emergent Serious Adverse Event (SAE) During the Treatment Phase (up to 113 Weeks) | Duration of the Treatment Phase (up to 113 weeks) | An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A Serious Adverse Event must meet 1 or more predefined criteria like death, life-threatening, etc. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Remaining Seizure Free for 12 Consecutive Months (52 Consecutive Weeks) Following Stabilization at the Last Evaluated Dose for Each Subject | 12 consecutive months of treatment following stabilization at the last evaluated dose for each subject | The proportion of subjects remaining seizure free for 12 months (52 weeks) was estimated using Kaplan-Meier methods. |
Countries
Australia, Belgium, Bulgaria, Canada, Czechia, Finland, France, Germany, Greece, Hungary, Italy, Japan, Latvia, Lithuania, Mexico, Philippines, Poland, Portugal, Romania, Russia, Slovakia, South Korea, Spain, Sweden, Switzerland, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This study started to enroll in April 2011 and concluded in August 2015.
Pre-assignment details
Participant Flow refers to the Safety Analysis Set which is defined as all randomized subjects who took at least 1 dose of study medication and is identical with the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Lacosamide * Strengths: 50 mg / 100 mg
* Form: tablets
* Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose
* Duration: up to 118 weeks | 444 |
| Carbamazepine-Controlled Release (CBZ-CR) * Strengths: 200 mg
* Form: tablets
* Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose
* Duration: up to 118 weeks | 442 |
| Total Title | 886 |
| Total | 1,772 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | AE, non-serious non-fatal | 40 | 58 |
| Overall Study | AE, serious fatal | 0 | 1 |
| Overall Study | Lack of Efficacy | 47 | 31 |
| Overall Study | Lost to Follow-up | 15 | 18 |
| Overall Study | Other Reason | 11 | 12 |
| Overall Study | Protocol Violation | 11 | 10 |
| Overall Study | SAE, fatal + SAE, non-fatal | 1 | 0 |
| Overall Study | SAE, non-fatal | 7 | 9 |
| Overall Study | SAE,non-fatal+AE,non-serious non-fatal | 0 | 1 |
| Overall Study | Withdrawal by Subject | 46 | 38 |
Baseline characteristics
| Characteristic | Lacosamide | Carbamazepine-Controlled Release (CBZ-CR) | Total Title |
|---|---|---|---|
| Age, Categorical <=18 years | 27 Participants | 19 Participants | 46 Participants |
| Age, Categorical >=65 years | 62 Participants | 57 Participants | 119 Participants |
| Age, Categorical Between 18 and 65 years | 355 Participants | 366 Participants | 721 Participants |
| Age, Continuous | 41.9 years STANDARD_DEVIATION 17.9 | 41.8 years STANDARD_DEVIATION 17.2 | 41.8 years STANDARD_DEVIATION 17.6 |
| Sex: Female, Male Female | 201 Participants | 210 Participants | 411 Participants |
| Sex: Female, Male Male | 243 Participants | 232 Participants | 475 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 165 / 444 | 181 / 442 |
| serious Total, serious adverse events | 36 / 444 | 46 / 442 |
Outcome results
Primary
Number of Subjects Who Withdraw From the Study Due to a Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks)
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
Time frame: Duration of the Treatment Phase (up to 113 weeks)
Population: Safety Analysis Set consisting of all randomized subjects who took at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lacosamide | Number of Subjects Who Withdraw From the Study Due to a Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks) | 47 Participants |
| Carbamazepine-Controlled Release (CBZ-CR) | Number of Subjects Who Withdraw From the Study Due to a Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks) | 69 Participants |
Primary
Number of Subjects With at Least One Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks)
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
Time frame: Duration of the Treatment Phase (up to 113 weeks)
Population: Safety Analysis Set consisting of all randomized subjects who took at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lacosamide | Number of Subjects With at Least One Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks) | 328 Participants |
| Carbamazepine-Controlled Release (CBZ-CR) | Number of Subjects With at Least One Treatment-emergent Adverse Event (AE) During the Treatment Phase (up to 113 Weeks) | 332 Participants |
Primary
Number of Subjects With at Least One Treatment-emergent Serious Adverse Event (SAE) During the Treatment Phase (up to 113 Weeks)
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A Serious Adverse Event must meet 1 or more predefined criteria like death, life-threatening, etc. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
Time frame: Duration of the Treatment Phase (up to 113 weeks)
Population: Safety Analysis Set consisting of all randomized subjects who took at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lacosamide | Number of Subjects With at Least One Treatment-emergent Serious Adverse Event (SAE) During the Treatment Phase (up to 113 Weeks) | 32 Participants |
| Carbamazepine-Controlled Release (CBZ-CR) | Number of Subjects With at Least One Treatment-emergent Serious Adverse Event (SAE) During the Treatment Phase (up to 113 Weeks) | 43 Participants |
Primary
Proportion of Subjects in the Full Analysis Set (FAS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject
The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods.
Time frame: 6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject
Population: Full Analysis Set (FAS), consisting of all randomized subjects who took at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lacosamide | Proportion of Subjects in the Full Analysis Set (FAS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject | 89.8 percentage of subjects |
| Carbamazepine-Controlled Release (CBZ-CR) | Proportion of Subjects in the Full Analysis Set (FAS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject | 91.1 percentage of subjects |
Comparison: This was a noninferiority assessment of Lacosamide versus Carbamazepine-CR for the proportion of subjects remaining seizure free for 6 months at the last evaluated dose.95% CI: [-5.5, 2.8]Mantel Haenszel
Primary
Proportion of Subjects in the Per Protocol Set (PPS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject
The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods.
Time frame: 6 consecutive months (26 consecutive weeks) of treatment
Population: The Per Protocol Set (PPS) was defined as containing all subjects in the Full Analysis Set (FAS) who did not have any important protocol deviations determined to impact the interpretation of primary efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lacosamide | Proportion of Subjects in the Per Protocol Set (PPS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject | 91.4 percentage of subjects |
| Carbamazepine-Controlled Release (CBZ-CR) | Proportion of Subjects in the Per Protocol Set (PPS) Remaining Seizure Free for 6 Consecutive Months (26 Consecutive Weeks) of Treatment Following Stabilization at the Last Evaluated Dose for Each Subject | 92.8 percentage of subjects |
Comparison: This was a noninferiority assessment of Lacosamide versus Carbamazepine-CR for the proportion of subjects remaining seizure free for 6 months at the last evaluated dose.95% CI: [-5.3, 2.7]Mantel Haenszel
Secondary
Proportion of Subjects Remaining Seizure Free for 12 Consecutive Months (52 Consecutive Weeks) Following Stabilization at the Last Evaluated Dose for Each Subject
The proportion of subjects remaining seizure free for 12 months (52 weeks) was estimated using Kaplan-Meier methods.
Time frame: 12 consecutive months of treatment following stabilization at the last evaluated dose for each subject
Population: Full Analysis Set (FAS), consisting of all randomized subjects who took at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lacosamide | Proportion of Subjects Remaining Seizure Free for 12 Consecutive Months (52 Consecutive Weeks) Following Stabilization at the Last Evaluated Dose for Each Subject | 77.8 percentage of subjects |
| Carbamazepine-Controlled Release (CBZ-CR) | Proportion of Subjects Remaining Seizure Free for 12 Consecutive Months (52 Consecutive Weeks) Following Stabilization at the Last Evaluated Dose for Each Subject | 82.7 percentage of subjects |