Partial Epilepsy
Conditions
Brief summary
This is a multicenter, double-blind, randomized, placebo-controlled dose response study, with an 8-week prospective baseline and an 18 week double-blind treatment period (including a 6-week titration phase and 12 week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects who will participate in the open-label extension). The primary objective of this study is to determine the effective dose range of YKP3089 as adjunctive therapy for the treatment of partial seizures. The trial will also evaluate the safety and tolerability of YKP3089 in the partial epilepsy population.
Interventions
DRUGYKP3089
DRUGPlacebo
Sponsors
SK Life Science, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Weight at least 40 kg * A diagnosis of partial epilepsy according to the International League Against Epilepsy's Classification of Epileptic Seizures. Diagnosis should have been established by clinical history and an electroencephalogram (EEG) that is consistent with localization related epilepsy; normal interictal EEGs will be allowed provided that the subject meets the other diagnosis criterion (ie, clinical history) * Have uncontrolled partial seizures despite having been treated with at least 1 AED within approximately the last 2 years * During the 8-week baseline period, subjects must have at least 8 partial seizures including only simple partial seizures with motor component, complex partial seizures, or secondarily generalized seizures without a seizure-free interval of greater than 25 days any time during the 8 weeks baseline. Subjects must have at least 3 of these partial seizures during each of the two consecutive 4-week segments of the baseline period * Currently on stable antiepileptic treatment regimen.
Exclusion criteria
* A history of nonepileptic or psychogenic seizures * Presence of only nonmotor simple partial seizures or primary generalized epilepsies * Presence or previous history of Lennox-Gastaut syndrome * An active CNS infection, demyelinating disease, degenerative neurologic disease, or any CNS disease deemed to be progressive during the course of the study that may confound the interpretation of the study results * Any clinically significant psychiatric illness, psychological, or behavioral problems that, in the opinion of the Investigator, would interfere with the subject's ability to participate in the study * History of alcoholism, drug abuse, or drug addiction within the past 2 years * History of status epilepticus within 3 months of Visit 1 * A yes answer to Question 1 or 2 of the C-SSRS (Baseline/Screening version) Ideation Section in the past 6 months or a yes answer to any of the Suicidal Behavior Questions in the past 2 years * More than 1 lifetime suicide attempt * Participation in any other trials involving an investigational product or device within 30 days of screening (or longer, as required by local regulations) * A history of any previous exposure to YKP3089
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Partial-onset Seizure Frequency Per 28 Days | baseline and 18 weeks | Percent change in complex partial and/or secondarily generalized and/or simple partial motor seizure frequency per 28 days (average 28-day seizure rate) in each treatment group during the double-blind period relative to the pretreatment baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 50% Responder Rate | 18 weeks | Percentage of patients achieving a 50% or more reduction from baseline in partial seizure frequency during the double-blind treatment period |
Countries
Australia, Bulgaria, Czechia, France, Germany, Hungary, Israel, Poland, Romania, Serbia, South Korea, Spain, Thailand, Ukraine, United States
Participant flow
Pre-assignment details
533 subjects were screened and 96 were excluded for the following reasons: did not meet eligibility criteria (n=83) and withdrew consent (n=13).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects treated with identical appearing study drug. | 108 |
| Cenobamate 100 mg/Day Subjects titrated to a target dose of 100 mg/day | 108 |
| Cenobamate 200 mg/Day Subjects titrated to a target dose of 200 mg/day | 110 |
| Cenobamate 400 mg/Day Subjects titrated to a target dose of 400 mg/day | 111 |
| Total | 437 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Period of Study YKP3089C017 | Adverse Event | 5 | 12 | 15 | 23 |
| Double-blind Period of Study YKP3089C017 | Lack of Efficacy | 0 | 1 | 0 | 1 |
| Double-blind Period of Study YKP3089C017 | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Double-blind Period of Study YKP3089C017 | Pregnancy | 1 | 0 | 0 | 0 |
| Double-blind Period of Study YKP3089C017 | Protocol Violation | 0 | 0 | 1 | 1 |
| Double-blind Period of Study YKP3089C017 | Reason Unknown | 3 | 0 | 0 | 1 |
| Double-blind Period of Study YKP3089C017 | Withdrawal by Subject | 5 | 0 | 4 | 3 |
| Open-label Extension Study YKP3089C017 | Adverse Event | 9 | 6 | 6 | 7 |
| Open-label Extension Study YKP3089C017 | Death | 1 | 1 | 3 | 2 |
| Open-label Extension Study YKP3089C017 | Entered Expanded Access Program | 30 | 39 | 28 | 32 |
| Open-label Extension Study YKP3089C017 | Lack of Efficacy | 13 | 17 | 23 | 14 |
| Open-label Extension Study YKP3089C017 | Lost to Follow-up | 2 | 1 | 1 | 3 |
| Open-label Extension Study YKP3089C017 | Protocol Violation | 1 | 0 | 0 | 2 |
| Open-label Extension Study YKP3089C017 | Reason Unknown | 3 | 3 | 1 | 3 |
| Open-label Extension Study YKP3089C017 | Withdrawal by Subject | 16 | 7 | 9 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Cenobamate 400 mg/Day | Cenobamate 200 mg/Day | Cenobamate 100 mg/Day |
|---|---|---|---|---|---|
| 28-day partial-onset seizure frequency | 8.4 seizures/28 days | 9.4 seizures/28 days | 9.0 seizures/28 days | 11.0 seizures/28 days | 9.5 seizures/28 days |
| Age, Continuous | 38 Years | 38 Years | 38.0 Years | 40.5 Years | 37.5 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 37 Participants | 13 Participants | 7 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 99 Participants | 400 Participants | 98 Participants | 103 Participants | 100 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 41 Participants | 11 Participants | 11 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 12 Participants | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 12 Participants | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) White | 93 Participants | 372 Participants | 96 Participants | 94 Participants | 89 Participants |
| Sex: Female, Male Female | 50 Participants | 216 Participants | 59 Participants | 56 Participants | 51 Participants |
| Sex: Female, Male Male | 58 Participants | 221 Participants | 52 Participants | 54 Participants | 57 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 / 108 | 0 / 108 | 0 / 110 | 0 / 111 | 1 / 95 | 3 / 90 | 3 / 80 | 2 / 91 |
| other Total, other adverse events | 76 / 108 | 70 / 108 | 84 / 110 | 100 / 111 | 87 / 95 | 80 / 90 | 70 / 70 | 80 / 80 |
| serious Total, serious adverse events | 6 / 108 | 10 / 108 | 4 / 110 | 8 / 111 | 21 / 95 | 17 / 90 | 21 / 80 | 20 / 91 |
Outcome results
Primary
Percent Change From Baseline in Partial-onset Seizure Frequency Per 28 Days
Percent change in complex partial and/or secondarily generalized and/or simple partial motor seizure frequency per 28 days (average 28-day seizure rate) in each treatment group during the double-blind period relative to the pretreatment baseline.
Time frame: baseline and 18 weeks
Population: All randomly assigned patients who took at least one dose of study drug and had any post-baseline seizure data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Partial-onset Seizure Frequency Per 28 Days | -24.0 percent change |
| Cenobamate 100 mg/Day | Percent Change From Baseline in Partial-onset Seizure Frequency Per 28 Days | -35.5 percent change |
| Cenobamate 200 mg/Day | Percent Change From Baseline in Partial-onset Seizure Frequency Per 28 Days | -55.0 percent change |
| Cenobamate 400 mg/Day | Percent Change From Baseline in Partial-onset Seizure Frequency Per 28 Days | -55.0 percent change |
Comparison: A step down procedure was used for the primary efficacy analyses to ensure the type one error rate for multiple comparisons was controlled at the 5% level using the following hierarchy: 200 mg vs placebo, 400 mg vs placebo, 100 mg vs placebo, in which a statistically significant difference had to be detected in this order for each subsequent comparison to occur.p-value: <0.001ANCOVA
p-value: <0.001ANCOVA
p-value: 0.007ANCOVA
Secondary
50% Responder Rate
Percentage of patients achieving a 50% or more reduction from baseline in partial seizure frequency during the double-blind treatment period
Time frame: 18 weeks
Population: All randomly assigned patients who had taken at least one dose of study drug and had any post-baseline seizure data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 50% Responder Rate | 23 Participants |
| Cenobamate 100 mg/Day | 50% Responder Rate | 44 Participants |
| Cenobamate 200 mg/Day | 50% Responder Rate | 63 Participants |
| Cenobamate 400 mg/Day | 50% Responder Rate | 67 Participants |
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
p-value: 0.003Fisher Exact