Clinical trial NCT04836559: A Study to Investigate JNJ-40411813 in Combination With Levetiracetam or Brivaracetam in Epilepsy
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Focal Onset Seizures
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2021-04-08
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to Baseline Monthly Seizure Count up to the end of the 12-week Double-blind Treatment Period
timeFrame: Baseline to 12 weeks
measure: Open Label Extension (OLE) Period: Seizure Count
timeFrame: Up to 2 years in OLE period
measure: OLE Period: Number of Participants with Adverse Events (AEs)
timeFrame: Up to 2 years in OLE period
measure: OLE Period: Number of Participants with Clinically Significant Changes in Vital Signs
timeFrame: Up to 2 years in OLE period
measure: OLE Period: Number of Participants with Clinically Significant Changes in Laboratory Assessments
timeFrame: Up to 2 years in OLE period
Secondary outcomes:
measure: Double Blind Treatment Period: Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability
timeFrame: Up to 22 weeks
measure: Double Blind Treatment Period: Number of Participants with Clinically Significant Changes in Laboratory Results
timeFrame: Up to 12 weeks
measure: Double Blind Treatment Period: Number of Participants with Clinically Significant Changes in Vital Signs
timeFrame: Up to 12 weeks
measure: Double Blind Treatment Period: Number of Participants with Clinically Significant Changes in Electrocardiogram (ECG) Results
timeFrame: Up to 12 weeks
measure: Double Blind Treatment Period: Percent reduction in the Double-blind Monthly Seizure Count
timeFrame: Baseline, up to 12 weeks
measure: 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
timeFrame: Baseline, up to 12 weeks
measure: Double Blind Treatment Period: Plasma Concentration of JNJ-40411813
timeFrame: Baseline (Day 1), Weeks 4, 8, and 12
measure: Double Blind Treatment Period: Plasma Concentration of Levetiracetam or Brivaracetam
timeFrame: Baseline (Day 1), Weeks 4, 8, and 12
measure: OLE Period: Plasma Concentration of JNJ-40411813
timeFrame: Up to 1 year in OLE period
measure: OLE Period: Plasma Concentration of Anti-epileptic Drugs (AEDs)
timeFrame: Up to 1 year in OLE period
measure: OLE Period: Plasma Concentration of Levetiracetam or Brivaracetam
timeFrame: Up to 1 year in OLE period
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Tucson Neuroscience Research
state: Arizona
city: Orlando
country: United States
facility: Research Institution of Orlando, LLC
state: Florida
city: Port Orange
country: United States
facility: Accel Research Sites
state: Florida
city: Scarborough
country: United States
facility: Maine Medical Center
state: Maine
city: Bethesda
country: United States
facility: Mid-Atlantic Epilepsy and Sleep Center
state: Maryland
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Brugge
country: Belgium
facility: AZ Sint-Jan
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint Luc
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Kortrijk
country: Belgium
facility: Az Groeninge
city: Leuven
country: Belgium
facility: UZ Leuven
city: Yvoir
country: Belgium
facility: CHU UCL Namur - Site Godinne
city: Berlin
country: Germany
facility: Vivantes Humboldt Klinikum
city: Bielefeld
country: Germany
facility: Krankenhaus Mara - Bethel
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Erlangen
country: Germany
facility: Universitaetsklinik Erlangen
city: Frankfurt
country: Germany
facility: Universitaetsklinikum Frankfurt
city: Kehl-Kork
country: Germany
facility: Diakonie Kork - Epilepsiezentrum
city: Marburg
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Bydgoszcz
country: Poland
facility: Centrum Medyczne Neuromed Sp z o. o.
city: Gdansk
country: Poland
facility: Copernicus Podmiot Leczniczy Sp. z o.o
city: Katowice
country: Poland
facility: MA LEK AM Maciejowscy Spolka Cywilna Centrum Terapii SM
city: Katowice
country: Poland
facility: NEURO MEDIC Janusz Zbrojkiewicz Poradnia Wielospecjalistyczna
city: Katowice
country: Poland
facility: NZOZ Wielospecjalistyczna Poradnia Lekarska 'Synapsis'
city: Krakow
country: Poland
facility: Specjalistyczne Gabinety Lekarskie
city: Krakow
country: Poland
facility: Centrum Leczenia Padaczki i Migreny NZOZ
city: Ksawerow
country: Poland
facility: Centrum Opieki Zdrowotnej Orkan Med Stec Michalska sj
city: Lublin
country: Poland
facility: Clinical Best Solutions Sp. z o.o., Sp. K.
city: Nowa Sol
country: Poland
facility: Twoja Przychodnia - Centrum Medyczne Nowa Sol
city: Poznan
country: Poland
facility: Clinical Research Center sp z o o MEDIC R s k
city: Poznan
country: Poland
facility: NZOZ NEURO KARD Ilkowski i Partnerzy Sp Partnerska Lekarzy
city: Warszawa
country: Poland
facility: MTZ Clinical Research Powered by Pratia
city: Warszawa
country: Poland
facility: Neurosphera
city: Warszawa
country: Poland
facility: Institute of Psychiatry and Neurology
city: Wroclaw
country: Poland
facility: Centrum Medyczne Oporow
city: Zory
country: Poland
facility: ProNeuro Centrum Medyczne
city: Kazan
country: Russian Federation
facility: Republic Clinical Hospital
city: Kazan
country: Russian Federation
facility: Research Medical Center Your Health
city: Krasnodar
country: Russian Federation
facility: Specialized clinical psychiatric hospital #1
city: Moscow
country: Russian Federation
facility: Clinical City Hospital #1
city: Nizny Novgorod
country: Russian Federation
facility: Nizny Novgorod clinical psychiatric hospital 1
city: Saratov
country: Russian Federation
facility: SHI 'Saratov City Clinical Hospital 2 n.a V.I. Razumovsky
city: Smolensk
country: Russian Federation
facility: Smolensk Regional Clinical Hospital
city: St-Petersburg
country: Russian Federation
facility: Psychoneurological Dispensary of Frunzensky District
city: St-Petersburg
country: Russian Federation
facility: St-Petersburg Bekhterev Psychoneurological Research Institute
city: Yaroslavl
country: Russian Federation
facility: Yaroslavl State Medical University
city: Barcelona
country: Spain
facility: Hosp. Del Mar
city: Barcelona
country: Spain
facility: Hosp Univ Vall D Hebron
city: Barcelona
country: Spain
facility: Hosp Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hosp. de La Santa Creu I Sant Pau
city: Madrid
country: Spain
facility: Hosp. Univ. de La Princesa
city: Malaga
country: Spain
facility: Hosp Regional Univ de Malaga
city: Sevilla
country: Spain
facility: Centro Neurologia Avanzada Sevilla
city: Terrassa
country: Spain
facility: Hosp. Mutua Terrassa
city: Zaragoza
country: Spain
facility: Centro de Inv. Avanzada Neurociencias
city: Dnipro
country: Ukraine
facility: Ce 'Dnipropetrovsk Regional Clinical Hospital N.A. Mechnikov' of Dnipropetrovsk Rc
city: Kharkiv
country: Ukraine
facility: Medical Center of Private Enterprise Neuron
city: Lviv
country: Ukraine
facility: Cnce of Lviv Regional Council 'Lviv Regional Clinical Hospital'
city: Nove Settlement
country: Ukraine
facility: Mnpe 'Regional Clinical Psychiatric Hospital of Kirovohrad Regional Council'
city: Ternopil
country: Ukraine
facility: Mnce 'Ternopil Regional Clinical Psychoneurology Hospital' of Trb
city: Uzhhorod
country: Ukraine
facility: Llc Diamed Medical Center
city: Vinnytsya
country: Ukraine
facility: Cnpe 'Vinnytsia Regional Clinical Psycho-Neurological Hospital N.A. Ac. O.I. Yushchenko' of Vrc
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References: