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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 110
- 试验地点
- 69
- 主要终点
- Cohort 1 and 2: Time to Baseline Monthly Seizure Count up to the End of the 12-week Double-blind (DB) Treatment Period
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 69 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
JNJ-40411813
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.
干预措施: JNJ-40411813 (Drug)
Placebo
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.
干预措施: JNJ-40411813 (Drug)
Placebo
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Cohort 1 and 2: Time to Baseline Monthly Seizure Count up to the End of the 12-week Double-blind (DB) Treatment Period
时间窗: From DB period Day 1 up to Day 85
Time (in days) to baseline monthly seizure count was defined as the number of days until the participants cumulative seizure count during the DB period was equal to their baseline monthly seizure count. The baseline monthly seizure count was defined as the number of observable focal onset seizures occurred during the 8-week baseline period (Day -56 to -1), multiplied by 28/XBL, where XBL was the number of days comprising the participants baseline period. Observable focal onset seizures included 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 was not counted towards baseline monthly seizure count. Cluster seizures were counted as a single seizure. Kaplan-Meier method was used for the analysis.
次要结局
- DB Treatment Period: Cohort 1 and 2: Number of Participants With Treatment-emergent Clinically Important Changes in Electrocardiogram (ECG)(From DB period start (Day 1) up to 5 days after last dose of DB period (up to Day 90))
- OLE Period: Cohort 1 and 2: Plasma Concentration of AED: Brivaracetam(OLE visit 2: 1st month; OLE visit 3: 2nd month)
- Cohort 1 and 2: Percent Reduction in the Double-blind Period Monthly Seizure Rate(From DB period Day 1 up to Day 85)
- DB Treatment Period: Cohort 1 and 2: Plasma Concentration of AED: Levetiracetam(Day 1: pre-dose and 2 hours post-dose, Day 29: pre-dose and 1 hour post-dose, Day 57: pre-dose and Day 85: post-dose/Early withdrawal)
- Cohort 1 and 2: Percent Reduction in the Open Label Extension (OLE) Period Monthly Seizure Rate(From OLE baseline (Day 1 of OLE) up to 24 months after start of OLE (the actual OLE starting time varied for each participant))
- DB Treatment Period: Cohort 1 and 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)(From DB period start (Day 1) up to 5 days after last dose of DB period (up to Day 90))
- Cohort 1 and 2: Percentage of Participants With Seizure Freedom During Double-blind Period(From DB period Day 1 up to Day 85)
- Cohort 1 and 2: Number of Participants With Seizure Freedom at the End of OLE Period(From OLE baseline (Day 1 of OLE) up to 24 months after start of OLE (the actual OLE starting time varied for each participant))
- OLE Period: Cohort 1 and 2: Number of Participants With Treatment-emergent (TE) Clinically Important Changes in Vital Signs(From OLE baseline (Day 1 of OLE) up to 24 months + 5 days after start of OLE (the actual OLE starting time varied for each participant))
- DB Treatment Period: Cohort 1 and 2: Number of Participants With Treatment-emergent Clinically Important Changes in Vital Signs(From DB period start (Day 1) up to 5 days after last dose of DB period (up to Day 90))
- Cohort 1 and 2: Number of Participants With at Least 50 Percent (%) Reduction (Response) in the OLE Monthly Seizure Count(From OLE baseline (Day 1 of OLE) up to 24 months after start of OLE (the actual OLE starting time varied for each participant))
- OLE Period: Cohort 1 and 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)(From OLE baseline (Day 1 of OLE) up to 5 days after last dose of OLE period (5 days + 24 months after start of OLE) (the actual OLE starting time varied for each participant))
- OLE Period: Cohort 1 and 2: Number of Participants With Changes in Laboratory Assessments Recorded as TEAE(From OLE baseline (Day 1 of OLE) up to 24 months + 5 days after start of OLE (the actual OLE starting time varied for each subject))
- Cohort 1 and 2: Percentage of Participants Who Achieved a More Than (>) 50 Percent (%) Reduction (Response) in Double-blind Monthly Seizure Count Relative to Baseline Monthly Seizure Count(From DB period Day 1 up to Day 85)
- DB Treatment Period: Cohort 1 and 2: Plasma Concentration of JNJ-40411813 and Its Metabolites: M30, M45 and M47(Day 1: 2 hours post-dose, Days 29: pre-dose and 1 hour post-dose, Day 57: pre-dose and Day 85: post-dose/Early withdrawal (EW))
- OLE Period: Plasma Concentration of AED: Carbamazepine(OLE visit 2: 1st month; OLE visit 3: 2nd month)
- DB Treatment Period: Cohort 1 and 2: Number of Participants With Changes in Laboratory Assessments Recorded as TEAE(From DB period start (Day 1) up to 5 days after last dose of DB period (up to Day 90))
- OLE Period: Cohort 1 and 2: Plasma Concentration of JNJ-40411813 and Its Metabolites: M30, M45 and M47(Cohort 1:OLE visit 2 (1 month post OLE baseline[BL]), OLE visit 3 (2 months post OLE BL), OLE visit 4 to 7 (up to 1year post OLE BL);Cohort 2:OLE visit 2 (1 month post OLE BL), OLE visit 3 (2 months post OLE BL), OLE visit 4 to 5 (up to 1year post OLE BL))
- DB Treatment Period: Cohort 1 and 2: Plasma Concentration of AED: Brivaracetam(Day 1: pre-dose and 2 hours post-dose, Days 29: pre-dose and 1 hour post-dose, Day 57: pre-dose and Day 85: post-dose/Early withdrawal)
- DB Treatment Period: Cohort 1 and 2: Plasma Concentration of AED: Carbamazepine(Pre-dose: Day 1, Days 29, and Day 57)
- OLE Period: Cohort 1 and 2: Plasma Concentration of AED: Levetiracetam(OLE visit 2: 1st month; OLE visit 3: 2nd month)