A Study to Investigate JNJ-40411813 in Combination With Levetiracetam or Brivaracetam in Epilepsy

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of up to 3 dose levels of adjunctive JNJ-40411813 compared to placebo based on the time to baseline monthly seizure count in participants with focal onset seizures who are receiving levetiracetam or brivaracetam and up to 3 other anti-epileptic drugs (AEDs) (double-blind treatment period) and to evaluate the long-term efficacy and safety of adjunctive therapy with JNJ-40411813 in participants with epilepsy (open-label extension [OLE] period).

Detailed Description
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JNJ-40411813 is a positive allosteric modulator (PAM) of the metabotropic glutamate receptor-2 (mGlu2), which is abundantly expressed in the forebrain and cerebellum. The mGlu2 receptor functions as a presynaptic auto-receptor that, upon activation, decreases the release of the excitatory neurotransmitter glutamate. Positive allosteric modulation of a receptor will result in the direct enhancement of the agonist-induced signal while PAMs themselves have generally no or low intrinsic activity at the receptor. The net effect of JNJ-40411813 is hypothesized to be a normalization of hyper-glutamatergic transmission. JNJ-40411813 is being evaluated for the treatment of disorders of the central nervous systems (CNS), such as epilepsy, and has been evaluated in schizophrenia and anxious depression. This study will consist of 1 to a maximum of 3 cohorts. In each cohort, for each participant the study consists of a screening period (up to minus [-] 8 weeks), an 8-week prospective pretreatment baseline period, an up to 12-week double-blind treatment period and a 2-year OLE period or a follow-up telephone visit 2 weeks after the last dose of study intervention. Safety assessments including physical and neurological examination, vital signs, 12 lead electrocardiogram (ECG), clinical chemistry, hematology, and urinalysis will be performed. The total maximal duration of the study is up to 2 years and 5 months.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-40411813 as Adjunctive Therapy in Subjects With Focal Onset Seizures With Suboptimal Response to Levetiracetam or Brivaracetam

Conditions
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Focal Onset Seizures

Intervention / Treatment
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* Drug: JNJ-40411813
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) between 18 and 35 kilogram per meter square (kg/m^2, inclusive (BMI = weight/height^2). Minimum body weight should be 40-kilogram (kg) Established diagnosis of focal epilepsy, for at least 1 year using the International League Against Epilepsy (ILAE) criteria. Participants should not be enrolled if they are known to have had fewer than 3 or more than 100 seizures in any monthly period in the past 6 months. It is preferred that participants have experience in maintaining a seizure e-diary Must have had a neuroimaging procedure within 10 years, including a computed tomography (CT) scan or magnetic resonance imaging (MRI), that excluded a progressive neurologic disorder; these procedures may be performed within the 8-week baseline period Cohort 1: Current treatment with at least 1 and up to 4 anti-epileptic drugs (AEDs) (including levetiracetam), administered at stable dosage(s) for at least 1 month before screening, and no new AEDs added for the previous 2 months; these AEDs must remain unchanged throughout the pretreatment and double-blind treatment periods (with the exception of dosage reductions of concomitant AEDs because of suspected elevated AED levels or side effects) Cohort 2 and beyond: Current treatment with at least 1 and up to 4 AEDs (including levetiracetam or brivaracetam), administered at the appropriate dosage(s) and for a sufficient treatment period before screening. These AEDs must remain unchanged throughout the pretreatment and double-blind treatment periods (with the exception of dosage reductions of concomitant AEDs because of suspected elevated AED levels or side effects). Important note: screening of participants receiving brivaracetam will start when enrolling for Cohort 2 Currently showing inadequate response to levetiracetam, administered at the appropriate dosage(s) and for a sufficient treatment period, based on the judgment of the investigator Healthy based on clinical laboratory tests, physical examination, medical history, vital signs, and 12-lead ECG Men or women between 18 and 69 years old Exclusion Criteria: Have a generalized epileptic syndrome Diagnosis of Lennox-Gastaut Syndrome Currently experiencing seizures that cannot be counted accurately History of any current or past nonepileptic seizures, including psychogenic seizures Known allergies, hypersensitivity, or intolerance to placebo, JNJ-40411813 or its excipients Current treatment with vagus nerve stimulation, deep brain and cortical stimulation for 1 year or less Planned epilepsy surgery within the next 6 months or completed epilepsy surgery less than (<) 6 months ago Current treatment with vigabatrin History of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is considered cured with minimal risk of recurrence) Current or past (within the past year) major psychotic disorder, such as schizophrenia, bipolar disorder, or other psychotic conditions, recent (within the past 6 months) interictal psychosis, and major depressive disorder (MDD) with psychotic features Exacerbation of MDD within the past 6 months; antidepressant use is allowed Has a current or recent history of clinically significant suicidal ideation within the past 6 months, corresponding to a score of 4 (active suicidal ideation with some intent to act, without specific plan) or 5 (active suicidal ideation with specific plan and intent) for ideation on the Columbia Suicide Severity Rating Scale (C-SSRS), or a history of suicidal behavior within the past 1 year, as validated by the CSSRS at screening Has a history of at least mild drug or alcohol use disorder according to Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) criteria within 1 year before Screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JNJ-40411813<br>Participants will receive JNJ-40411813 twice a day (bid) up to 12 weeks in double blind period. Up to 3 different doses (low, medium, high) of JNJ-40411813 will be administered in this study. Participants will also receive concomitant anti-epileptic drugs (AEDs) one of which must include levetiracetam or brivaracetam. Immediately after the last study drug intake by the participants in the double-blind period, participants will enter into a 2-year open label extension (OLE) period and continue receiving JNJ-40411813 as well as the AEDs during OLE period. | Drug: JNJ-40411813<br>* JNJ-40411813 will be administered orally.<br>|
| Placebo Comparator: Placebo<br>Participants will receive JNJ-40411813 matching placebo (bid) up to 12 weeks. Participants will also receive concomitant AEDs one of which must include levetiracetam or brivaracetam during double blind period. Participants who had been receiving placebo in double blind period will start with the JNJ-40411813 dose in the OLE period. | Drug: JNJ-40411813<br>* JNJ-40411813 will be administered orally.<br>Drug: Placebo<br>* Placebo will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Baseline Monthly Seizure Count up to the end of the 12-week Double-blind Treatment Period | Time to baseline monthly seizure count is defined, for each participant, as the number of days until the participants experienced the number of seizures equal to baseline monthly seizure count, up to the end of the 12-week double-blind treatment period. Baseline monthly seizure count will be defined as the number of observable focal onset seizures recorded during the baseline period, multiplied by 28/ XBL, where XBL is the number of days comprising the baseline. | Baseline to 12 weeks | 
| Open Label Extension (OLE) Period: Seizure Count | Seizure count will be reported. Seizure count per 28 days will be calculated as (28/the number of days between visits)*(seizures counted between the visits). | Up to 2 years in OLE period | 
| OLE Period: Number of Participants with Adverse Events (AEs) | An AE is any untoward medical occurrence in a clinical study participant administered an investigational or non-investigational medicinal product. An AE does not necessarily have a causal relationship with the treatment. | Up to 2 years in OLE period | 
| OLE Period: Number of Participants with Clinically Significant Changes in Vital Signs | Number of participants with clinically significant changes in vital signs including blood pressure and oral or tympanic temperature will be reported. | Up to 2 years in OLE period | 
| OLE Period: Number of Participants with Clinically Significant Changes in Laboratory Assessments | Number of participants with clinically significant changes in laboratory assessments including hematology, serum chemistry, serology, and urinalysis will be reported. | Up to 2 years in OLE period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Double Blind Treatment Period: Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability | An AE is any untoward medical occurrence in a clinical study participant administered an investigational or non-investigational medicinal product. An AE does not necessarily have a causal relationship with the treatment. | Up to 22 weeks | 
| Double Blind Treatment Period: Number of Participants with Clinically Significant Changes in Laboratory Results | Number of participants with clinically significant changes in laboratory results related to hematology, serum chemistry, serology, and urinalysis will be reported. | Up to 12 weeks | 
| Double Blind Treatment Period: Number of Participants with Clinically Significant Changes in Vital Signs | Number of participants with clinically significant changes in vital signs including blood pressure and oral or tympanic temperature will be reported. | Up to 12 weeks | 
| Double Blind Treatment Period: Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Results | Number of participants with clinically significant changes in ECG results will be reported. | Up to 12 weeks | 
| Double Blind Treatment Period: Percent reduction in the Double-blind Monthly Seizure Count | Percent reduction in the double-blind monthly seizure count is defined as the double-blind monthly seizure count minus the baseline monthly seizure count, divided by the baseline monthly seizure count. The double-blind monthly seizure count is defined as the total number of observable focal onset seizures occurring during the 12-week double blind treatment period, multiplied by 28/XDB, where XDB is the number of days comprising the double-blind period. Observable seizures that will be counted during baseline and throughout the study include focal aware seizures with motor signs, focal impaired awareness seizures and focal to bilateral tonic-clonic seizures. Focal aware seizures without motor signs, myoclonic, or other generalized seizures will not be counted. | Baseline, up to 12 weeks | 
| Double Blind Treatment Period: Percentage of Participants with no Seizures During Double-blind Period and who Achieve a More than (>) 50 Percent (%) Reduction in Monthly Seizure Count Relative to Baseline Monthly Seizure Count | Percentage of participants with no seizures during double-blind period and who achieve a > 50% reduction in monthly seizure count relative to baseline monthly seizure count will be reported. | Baseline, up to 12 weeks | 
| Double Blind Treatment Period: Plasma Concentration of JNJ-40411813 | Plasma samples will be analyzed to determine concentration of JNJ-40411813 using a validated, specific, and sensitive liquid chromatography mass spectrometry/mass spectrometry (LC -MS/MS) methods. | Baseline (Day 1), Weeks 4, 8, and 12 | 
| Double Blind Treatment Period: Plasma Concentration of Levetiracetam or Brivaracetam | Plasma samples will be analyzed to determine concentration of levetiracetam or brivaracetam using a validated, specific, and sensitive LC -MS/MS methods. | Baseline (Day 1), Weeks 4, 8, and 12 | 
| OLE Period: Plasma Concentration of JNJ-40411813 | Plasma samples will be analyzed to determine concentration of JNJ-40411813 using a validated, specific, and sensitive liquid chromatography mass spectrometry/mass spectrometry (LC -MS/MS) methods. | Up to 1 year in OLE period | 
| OLE Period: Plasma Concentration of Anti-epileptic Drugs (AEDs) | Plasma samples will be analyzed to determine concentration of AEDs using a validated, specific, and sensitive LC-MS/MS methods. | Up to 1 year in OLE period | 
| OLE Period: Plasma Concentration of Levetiracetam or Brivaracetam | Plasma samples will be analyzed to determine concentration of levetiracetam or brivaracetam using a validated, specific, and sensitive LC MS/MS methods. | Up to 1 year in OLE period |