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

Focal Onset Seizures Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04836559
• Other study ID #: CR108943
• Secondary ID: 2020-003698-2440
• Status: Completed
• Phase: Phase 2
• Start date: May 18, 2021
• Est. completion date: February 8, 2024

Study information

• Verified date: March 2024
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: February 8, 2024
• Est. primary completion date: February 8, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 69 Years

Eligibility

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

Related Conditions & MeSH terms

• Focal Onset Seizures
• Seizures

Intervention

Drug:
• JNJ-40411813
JNJ-40411813 will be administered orally.
• Placebo
Placebo will be administered orally.

Locations

Country	Name	City	State
Belgium	AZ Sint-Jan	Brugge
Belgium	Cliniques Universitaires Saint Luc	Bruxelles
Belgium	UZ Antwerpen	Edegem
Belgium	Az Groeninge	Kortrijk
Belgium	UZ Leuven	Leuven
Belgium	CHU UCL Namur - Site Godinne	Yvoir
Germany	Vivantes Humboldt Klinikum	Berlin
Germany	Krankenhaus Mara - Bethel	Bielefeld
Germany	Universitatsklinikum Bonn	Bonn
Germany	Universitaetsklinik Erlangen	Erlangen
Germany	Universitaetsklinikum Frankfurt	Frankfurt
Germany	Diakonie Kork - Epilepsiezentrum	Kehl-Kork
Germany	Universitaetsklinikum Giessen und Marburg GmbH	Marburg
Korea, Republic of	Chungnam National University Hospital	Daejeon
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Konkuk University Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Poland	Centrum Medyczne Neuromed Sp z o. o.	Bydgoszcz
Poland	Copernicus Podmiot Leczniczy Sp. z o.o	Gdansk
Poland	Centrum Terapii SM	Katowice
Poland	NEURO-MEDIC Janusz Zbrojkiewicz Poradnia Wielospecjalistyczna	Katowice
Poland	NZOZ Wielospecjalistyczna Poradnia Lekarska 'Synapsis'	Katowice
Poland	Specjalistyczne Gabinety Lekarskie	Krakow
Poland	Centrum Leczenia Padaczki i Migreny. NZOZ	Kraków
Poland	Centrum Opieki Zdrowotnej Orkan-med Stec-Michalska sj	Ksawerów
Poland	Clinical Best Solutions Sp. z o.o., Sp. K.	Lublin
Poland	Twoja Przychodnia - Centrum Medyczne Nowa Sol	Nowa Sol
Poland	Clinical Research Center sp z o o MEDIC R s k	Poznan
Poland	NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partnerska Lekarzy	Poznan
Poland	Institute of Psychiatry and Neurology	Warszawa
Poland	MTZ Clinical Research Powered by Pratia	Warszawa
Poland	Neurosphera	Warszawa
Poland	Centrum Medyczne Oporow	Wroclaw
Poland	ProNeuro Centrum Medyczne	Zory
Russian Federation	Republic Clinical Hospital	Kazan
Russian Federation	Research Medical Center Your Health	Kazan
Russian Federation	Specialized clinical psychiatric hospital #1	Krasnodar
Russian Federation	Clinical City Hospital #1	Moscow
Russian Federation	Nizny Novgorod clinical psychiatric hospital 1	Nizny Novgorod
Russian Federation	SHI 'Saratov City Clinical Hospital 2 n.a V.I. Razumovsky	Saratov
Russian Federation	Smolensk Regional Clinical Hospital	Smolensk
Russian Federation	Psychoneurological Dispensary of Frunzensky District	St-Petersburg
Russian Federation	St-Petersburg Bekhterev Psychoneurological Research Institute	St-Petersburg
Russian Federation	Yaroslavl State Medical University	Yaroslavl
Spain	Hosp. Clinic de Barcelona	Barcelona
Spain	Hosp. de La Santa Creu I Sant Pau	Barcelona
Spain	Hosp. Del Mar	Barcelona
Spain	Hosp. Univ. Vall D Hebron	Barcelona
Spain	Hosp. Univ. de La Princesa	Madrid
Spain	Hosp. Regional Univ. de Malaga	Malaga
Spain	Centro Neurologia Avanzada Sevilla	Sevilla
Spain	Hosp. Mutua Terrassa	Terrassa
Spain	Centro de Inv. Avanzada Neurociencias	Zaragoza
Ukraine	Ce 'Dnipropetrovsk Regional Clinical Hospital N.A. Mechnikov' of Dnipropetrovsk Rc	Dnipro
Ukraine	Medical Center of Private Enterprise Neuron	Kharkiv
Ukraine	Cnce of Lviv Regional Council 'Lviv Regional Clinical Hospital'	Lviv
Ukraine	Mnpe 'Regional Clinical Psychiatric Hospital of Kirovohrad Regional Council'	Nove Settlement, Kropyvnytskyi
Ukraine	Mnce 'Ternopil Regional Clinical Psychoneurology Hospital' of Trb	Ternopil
Ukraine	Llc Diamed Medical Center	Uzhhorod
Ukraine	Cnpe 'Vinnytsia Regional Clinical Psycho-Neurological Hospital N.A. Ac. O.I. Yushchenko' of Vrc	Vinnytsya
United States	Mid-Atlantic Epilepsy and Sleep Center	Bethesda	Maryland
United States	University of Virginia	Charlottesville	Virginia
United States	Research Institution of Orlando, LLC	Orlando	Florida
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Accel Research Sites	Port Orange	Florida
United States	Maine Medical Center	Scarborough	Maine
United States	Tucson Neuroscience Research	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Belgium,  Germany,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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