Epilepsy With Partial On-set Seizures
Conditions
Keywords
epilepsy, seizures, partial on-set seizures
Brief summary
A study of a drug to be used in addition with another drug to treat adults with Uncontrolled Partial-onset Seizures
Detailed description
This is a 31-week, multicenter, 2-arm, prospective, open-label, non-randomized, Phase 4 study of eslicarbazepine acetate (ESL) as adjunctive therapy in adult subjects with a diagnosis of epilepsy with POS. Two groups of ESL-naïve subjects will be evaluated. The groups are defined as follows: * Arm 1 (ESL as first add-on): This group will include subjects who have been maintained on a regimen consisting of a stable dose of LEV or LTG for at least 1 month (28 days) prior to screening and who have not used any adjunctive treatment. * Arm 2 (ESL as later add-on): This group will include subjects who have been maintained on a regimen consisting of a stable dose of 1-2 AEDs (excluding oxcarbazepine \[OXC\]) for at least 1 month (28 days) prior to screening and who have used adjunctive treatment in the past. The Arm 1 subjects will allow an assessment of the efficacy and safety of ESL in subjects who are early in the course of their disease and being treated with one of the most common first line AEDs. The subjects in Arm 2 are similar to the subject population in the ESL Phase 3 adjunctive epilepsy studies, treatment-resistant subjects who are later in the course of their disease. The inclusion of these subjects in the present study will provide an assessment of the efficacy and safety of ESL as a later adjunctive therapy in a real world clinical setting. In addition, this study will provide data from both Arm 1 and Arm 2 for several behavioral, mood-related, and QOL-related assessments that were not evaluated in the ESL Phase 3 adjunctive epilepsy program. The study will consist of a Screening Phase of 1 to 2 weeks, followed by a 2-week Titration Phase, a 24-week Maintenance Phase, and a Safety Follow-up/Taper Phase of 4 weeks. The last visit in the Maintenance Phase (Visit 9) is considered the End of Study (EOS) visit
Interventions
eslicarbazepine acetate tablets, taken once daily. Subjects begin 2-week Titration Phase starting on Day 1 (Week 1), by initiating treatment with ESL 400 mg/day. Subjects titrate to minimum dose of 800 mg/day for the 24-week Maintenance Phase beginning at Week 3. In the Maintenance Phase, subjects may titrate in weekly increments of 400 mg/day as medically indicated at the discretion of Investigator up to a maximum dose of 1200 mg/day (Canadian sites) or 1600 mg/day (US sites)
eslicarbazepine acetate acetate tablets, taken once daily. Subjects begin 2-week Titration Phase starting on Day 1 (Week 1), by initiating treatment with ESL 400 mg/day. Subjects titrate to minimum dose of 800 mg/day for the 24-week Maintenance Phase beginning at Week 3. In the Maintenance Phase, subjects may titrate in weekly increments of 400 mg/day as medically indicated at the discretion of Investigator up to a maximum dose of 1200 mg/day (Canadian sites) or 1600 mg/day (US sites)
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
open label
Intervention model description
Arm 1 (ESL as first add-on) Arm 2 (ESL as later add-on)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female subjects ≥ 18 years of age. 2. Subject is willing and able to sign informed consent. 3. Subject has a documented diagnosis of epilepsy with simple POS with a motor component or complex POS with or without secondarily generalized seizures as defined in the Classification of Seizures of the International League Against Epilepsy 4. Subject has a documented electroencephalogram within 10 years prior to screening. 5. Subject has had at least 3 POS during previous six months. 6. Subject has had a sufficient number of seizures at time of enrollment to justify adjunctive therapy, as determined by the Investigator. 7. Subjects are required to be ESL-naïve AND 1. Maintained on a stable LEV or LTG regimen for at least 1 month (28 days) prior to screening with no history of adjunctive treatment (for Arm 1, ESL as first add-on). OR 2. Maintained on a stable dose of 1-2 AEDs (excluding OXC) for at least 1 month (28 days) prior to screening and who have had prior adjunctive treatment (for Arm 2, ESL as later add-on). 8. If the subject is treated with any stimulation device for epilepsy Vagal Nerve Stimulation (VNS), Responsive Neurostimulator (RNS), or similar, the device must have been implanted at least 6 months before screening and the device parameters must be documented as stable for at least 1 month prior to screening. (Note: These devices will not be counted as concomitant AED). 9. Except for epilepsy, subject is judged to be in general good health based on medical history, physical examination findings, and clinical laboratory
Exclusion criteria
1. Subjects with a prior exposure to ESL. 2. Subjects currently being treated with OXC. 3. Subject with a history of allergic reaction to OXC or CBZ, or a history of serious allergic reaction (Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms or similar) to any AED, or a history of serious allergic reactions to other medications. 4. Subjects who have taken warfarin, felbamate, vigabatrin, or perampanel, (unless at stable dose with safety testing for ≥ 1 year) within a 4-week period prior to screening. 5. Subjects taking ezogabine . 6. Subject has taken any medication prohibited for this protocol within 4 weeks prior to Screening 7. Subjects using benzodiazepines on more than an occasional basis (defined as more than 2 times per week), except when used chronically as an AED 8. Seizure disorder characterized primarily by simple POS without motor signs. 9. Subject has a history of primarily generalized seizures (eg, myoclonic, absence, tonic). 10. Subject has a history of status epilepticus or cluster seizures (ie, 3 or more seizures within 30 minutes) within the 3 months prior to screening. 11. Subject has had seizures of psychogenic origin or purely subjective seizures within the last 2 years. 12. Subject has had seizures too close to count accurately. 13. Subject has a known progressive structural central nervous system (CNS) lesion, progressive encephalopathy or any other condition that may result in epilepsy secondary to a cerebral abnormality. 14. Subject whose current seizures are related to an acute medical illness or other non-epileptic origin. 15. Subjects of Asian ancestry will be excluded if they are carriers of HLA-B\*1502. Either: 1. Subject must give written informed consent for genotyping, and test negative. OR 2. Subjects must provide documentation of prior testing confirming non-carrier status. 16. Subject has a major medical illness other than epilepsy that would prevent safe participation in this study, at the discretion of the Investigator, including (but not limited to) cardiac disease, thyroid disease, hepatic or renal impairment, endocrine or metabolic disease, gastrointestinal disease, or hematologic disease. Note: Active medical conditions that are minor or well-controlled are not exclusionary if they do not affect risk to the subject or the study results. If the effect of the condition in regard to the risk to the subject or to the study results is unclear, the Medical Monitor should be consulted. 17. Subjects with clinically relevant laboratory abnormalities at screening (eg, sodium \< 130 mEq/L, alanine transaminase (ALT) or aspartate transaminase (AST) \> 2.0 times the upper limit of the normal, white blood cell \[WBC\] count \< 3,000 cells/mm3, estimated creatinine clearance \< 50 mL/min, or has values for thyroid testing (free triiodothyronine (T3), free thyroxine (T4), thyroid stimulating hormone \[TSH\]) indicating the presence of significant thyroid dysfunction. 18. Subject has a history or presence of abnormal electrocardiogram (ECG), which in the Investigator's opinion is clinically significant or QT interval corrected for heart rate using the Fridericia method (QTcF) of ≥ 450 msec per screening ECG. 19. Subject has second or third-degree atrioventricular block that is not corrected with a pacemaker. 20. Subjects who meet the Diagnostic and Statistical Manual of Mental Disorders, 5th edition text revision defined criteria for major depressive episode within the last 6 months. Subjects with mild, chronic depression without recent hospitalization who are being maintained on a stable dose of a single antidepressant are acceptable. 21. Subject has an active suicidal plan or intent (in the Investigator's opinion) in the past 4 weeks prior to screening. 22. Subject has a history of suicide attempt in the last 2 years prior to screening. 23. Subject has other major psychiatric disorders. 24. Subjects who are not able to complete the diary in the Investigator's opinion. 25. Subject has a history of alcohol or substance abuse within 2 years prior to screening for study participation, or subjects currently using alcohol, drugs of abuse, or any prescribed or over-the-counter medication in a manner, which, in the opinion of the Investigator, indicates abuse. 26. Subject tests positive for drugs of abuse at screening. Note: Subjects with a positive drug screen for marijuana, amphetamines, opiates, or benzodiazepines, who have a documented prescription for a medical condition and are on a stable dose of this prescribed medication for at least 4 weeks prior to screening, may be eligible to participate in the study upon approval from the Medical Monitor. 27. Subject is pregnant, currently nursing, or intends to become pregnant during the study period or within 30 days of the last dose of study drug. 28. Subject has participated in any investigational study within 30 days prior to screening, as documented in subject's medical history. 29. Subject is a clinical or investigational site staff member or relative of a staff member. 30. Any other condition or circumstance that, in the opinion of the Investigator, may compromise the subject's ability to comply with the study protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Subjects Completing 24 Weeks Adjunctive Therapy During Maintenance Phase | From the date of the first dose of the study drug until the completion of 24 weeks Maintenance Phase | Phase 4 study of eslicarbazepine acetate (ESL) as adjunctive therapy in adult subjects with a diagnosis of epilepsy with Partial-onset seizures (POS). Two groups of ESL-naïve subjects will be evaluated |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 (arm 1) Eslicarbazepine Acetate (ESL) as first add-on to Levetiracetam or Lamotrigine) | 44 |
| Arm 2 (arm 2) Eslicarbazepine Acetate (ESL) as later add-on to 1-2 Anti-epileptic drugs (AEDs) | 58 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 10 |
| Overall Study | OTHER | 3 | 3 |
| Overall Study | Withdrawal by Subject | 4 | 8 |
Baseline characteristics
| Characteristic | Arm 2 | Total | Arm 1 |
|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 2 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 9 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 91 Participants | 38 Participants |
| Age, Continuous | 42.0 Years STANDARD_DEVIATION 13.83 | 42.5 Years STANDARD_DEVIATION 14.45 | 43.1 Years STANDARD_DEVIATION 15.37 |
| Age, Customized >=18 - <=65 years | 55 Participants | 95 Participants | 40 Participants |
| Age, Customized > 65 years | 3 Participants | 7 Participants | 4 Participants |
| Baseline BMI (kg/m^2) | 30.83 kg/m^2 STANDARD_DEVIATION 7.618 | 29.97 kg/m^2 STANDARD_DEVIATION 6.895 | 28.83 kg/m^2 STANDARD_DEVIATION 5.694 |
| Baseline Height (cm) | 166.8 cm STANDARD_DEVIATION 9.73 | 166.9 cm STANDARD_DEVIATION 10.59 | 166.9 cm STANDARD_DEVIATION 11.76 |
| Baseline Weight (kg) | 86.24 kg STANDARD_DEVIATION 23.841 | 83.65 kg STANDARD_DEVIATION 21.151 | 80.23 kg STANDARD_DEVIATION 16.62 |
| Country Canada | 3 Participants | 3 Participants | 0 Participants |
| Country United States | 55 Participants | 99 Participants | 44 Participants |
| Duration of Epilepsy < 20 years | 36 Participants | 73 Participants | 37 Participants |
| Duration of Epilepsy >= 20 years | 22 Participants | 29 Participants | 7 Participants |
| Duration of Epilepsy (years) | 19.5 years STANDARD_DEVIATION 15.9 | 15.1 years STANDARD_DEVIATION 14.85 | 9.4 years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 14 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 88 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Number of Anti-epileptic drugs (AEDs) at Baseline 0 | 0 Participants | 1 Participants | 1 Participants |
| Number of Anti-epileptic drugs (AEDs) at Baseline 1 | 21 Participants | 63 Participants | 42 Participants |
| Number of Anti-epileptic drugs (AEDs) at Baseline >=2 | 37 Participants | 38 Participants | 1 Participants |
| Number of Anti-epileptic drugs (AEDs) at Baseline | 1.7 number of Anti-epileptic drugs (AEDs) STANDARD_DEVIATION 0.62 | 1.4 number of Anti-epileptic drugs (AEDs) STANDARD_DEVIATION 0.6 | 1 number of Anti-epileptic drugs (AEDs) STANDARD_DEVIATION 0.22 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 24 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 8 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Other | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 36 Participants | 64 Participants | 28 Participants |
| Rescue Medications at Baseline No | 53 Participants | 95 Participants | 42 Participants |
| Rescue Medications at Baseline Yes | 5 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Female | 36 Participants | 60 Participants | 24 Participants |
| Sex: Female, Male Male | 22 Participants | 42 Participants | 20 Participants |
| Use of Carbamazepine as Baseline AED No | 53 Participants | 97 Participants | 44 Participants |
| Use of Carbamazepine as Baseline AED Yes | 5 Participants | 5 Participants | 0 Participants |
| Use of Lacosamide as Baseline AED No | 47 Participants | 91 Participants | 44 Participants |
| Use of Lacosamide as Baseline AED Yes | 11 Participants | 11 Participants | 0 Participants |
| Use of Lamotrigine as Baseline AED No | 38 Participants | 67 Participants | 29 Participants |
| Use of Lamotrigine as Baseline AED Yes | 20 Participants | 35 Participants | 15 Participants |
| Use of Levetiracetam as Baseline AED No | 34 Participants | 50 Participants | 16 Participants |
| Use of Levetiracetam as Baseline AED Yes | 24 Participants | 52 Participants | 28 Participants |
| Use of Topiramate as Baseline AED No | 49 Participants | 93 Participants | 44 Participants |
| Use of Topiramate as Baseline AED Yes | 9 Participants | 9 Participants | 0 Participants |
| Use of Valproate All Forms as BL AED No | 47 Participants | 91 Participants | 44 Participants |
| Use of Valproate All Forms as BL AED Yes | 11 Participants | 11 Participants | 0 Participants |
| Use of Valproate Semisodium as BL AED No | 51 Participants | 95 Participants | 44 Participants |
| Use of Valproate Semisodium as BL AED Yes | 7 Participants | 7 Participants | 0 Participants |
| Use of Valproic Acid as Baseline AED No | 54 Participants | 98 Participants | 44 Participants |
| Use of Valproic Acid as Baseline AED Yes | 4 Participants | 4 Participants | 0 Participants |
| Worst Seizure Type during Baseline Complex Partial | 41 Participants | 66 Participants | 25 Participants |
| Worst Seizure Type during Baseline Other | 0 Participants | 1 Participants | 1 Participants |
| Worst Seizure Type during Baseline Partial Evolving to Secondary Generalized | 12 Participants | 24 Participants | 12 Participants |
| Worst Seizure Type during Baseline Simple Partial | 4 Participants | 10 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 58 |
| other Total, other adverse events | 21 / 44 | 36 / 58 |
| serious Total, serious adverse events | 0 / 44 | 4 / 58 |
Outcome results
Primary
The Number of Subjects Completing 24 Weeks Adjunctive Therapy During Maintenance Phase
Phase 4 study of eslicarbazepine acetate (ESL) as adjunctive therapy in adult subjects with a diagnosis of epilepsy with Partial-onset seizures (POS). Two groups of ESL-naïve subjects will be evaluated
Time frame: From the date of the first dose of the study drug until the completion of 24 weeks Maintenance Phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eslicarbazepine Acetate (Arm 1) | The Number of Subjects Completing 24 Weeks Adjunctive Therapy During Maintenance Phase | 36 participants |
| Eslicarbazepine Acetate (Arm 2) | The Number of Subjects Completing 24 Weeks Adjunctive Therapy During Maintenance Phase | 37 participants |