Clinical trial NCT04244175: A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures
Official title: A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Trial of CVL-865 as Adjunctive Therapy in Adults With Drug-Resistant Focal Onset Seizures (REALIZE Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Seizures
Keywords: CVL-865
Anti-epileptic drugs (AEDs)
Focal epilepsy
γ-aminobutyric acid (GABA)
Partial seizure
PF-06372865
Darigabat
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
First posted: 2020-01-28
Enrollment: 154
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to learn if CVL-865, when taken regularly with other anti-seizure medicines, works to prevent seizures in adults with drug-resistant focal onset seizures. It will also learn about the safety of CVL-865.

The main question it aims to answer is whether CVL-865, when taken regularly with other anti-seizure medicines, lowers the number of seizures in those with a diagnosis of epilepsy with drug-resistant focal onset seizures.

This study has an 8-week Screening/Baseline Period, a 13-week Treatment Period (including a 2-week Titration Phase, an 8-week Maintenance Phase, and a 3-week Taper Phase), and a 4-week Safety Follow-Up Period.

Participants will take CVL-865 or a placebo twice a day during the 10-13 week Treatment Period, visit the clinic every few weeks for checkups, tests, and surveys, and fill out an e-Diary.


Eligibility criteria: Inclusion Criteria:

* Participants with a diagnosis of epilepsy with focal onset, as defined in the International League Against Epilepsy (ILAE) Classification of Seizures, focal aware (except participants with only focal aware seizures without a motor component), focal impaired awareness, and focal to bilateral tonic-clonic seizures for at least 2 years prior to signing the Informed Consent Form (ICF)
* Participants must have history of an average of 4 or more spontaneous and observable focal onset, as defined in the ILAE Classification of Seizures, focal aware (except participants with only focal aware seizures without a motor component), focal impaired awareness, and focal to bilateral tonic-clonic seizures per 28-day period for at least 3 months (84 days) prior to signing the ICF
* Participants who have tried and failed at least 2 appropriate Anti- epileptic drugs (AEDs) in the past and also currently taking 1 to 3 permitted AEDs at a stable dose for 4 Weeks prior to the Screening Visit
* Participants with a minimum of 8 focal onset, focal aware, focal impaired awareness, or focal to bilateral tonic-clonic seizures during the 8 week baseline period with no 21-day period free of any of these seizure types
* Participants must have had magnetic resonance imaging or contrast enhance computed tomography scan of the brain that demonstrated no progressive structural central nervous system abnormality at the time of the diagnosis of epilepsy
* Participants must have a body mass index (BMI) of 17.5 to 40.0 kilogram per meter square (kg/m\^2) and a total body weight greater than (\>) 50 kilograms (kg) \[110 pounds (lbs)\]
* Women of childbearing potential must agree to use an effective method of contraception from signing of informed consent throughout the duration of the study and for 30 days post last dose
* Male must agree to use condom during treatment and until the end of relevant systemic exposure in the male participant for 94 days following the last dose with Investigational Manufacturing Product (IMP)

Exclusion Criteria:

* Participants with (genetic) idiopathic generalized epilepsies or combined generalized and focal epilepsies, including a history of Lennox-Gastaut Syndrome
* Participants with a history of seizures over the past 12 months that occur at such a high frequency they cannot be counted (eg, repetitive seizures, cluster seizures)
* Participants with a history of psychogenic non-epileptic seizures within the year prior to signing the ICF
* Participants with a history of status epilepticus within 5 years prior to signing the ICF
* Participants with a history of neurosurgery for seizures less than 1 year prior to signing the ICF, or radiosurgery less than 2 years prior to signing the ICF
* Participants with a current history of significant cardiovascular, pulmonary, gastrointestinal, renal, hepatic, metabolic, hematological, immunological, or neurological (excluding focal onset epilepsy) disease
* Participants who test positive for human immunodeficiency virus (HIV), hepatitis B and/or or hepatitis C infection
* Participants with a 12-lead ECG demonstrating : QT interval corrected for heart rate using Fridericia's formula \>450 milliseconds (msec) (average of 3 ECGs obtained at the Screening Visit); QRS interval \>120 msec at the Screening Visit assessed by central reader
* Participants with abnormal laboratory test results which includes (Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) elevated to \>2 × Upper limit of normal range (ULN); Total bilirubin greater than or equal to (\>=)1.5 × ULN; Females: Hemoglobin \<11 gram per deciliter (g/dL); Males: hemoglobin \<12 g/dL; White blood cell (WBC) count \<3.0 x 10 power 9 per liter (10\^9/L); Neutrophil count \<2.0 x 10\^9/L; Platelet count \<150 × 10\^9/L
* Use of prohibited medications as listed in the protocol in the absence of appropriate washout phase or the likelihood of requiring treatment during the study period with drugs not permitted by the study protocol
* Participants taking any drug that is a sensitive P-glycoprotein (P-gp) and Breast cancer resistance protein (BCRP) substrate
* Female participants who are breastfeeding and/or who have a positive pregnancy test result prior to receiving IMP
* Participants who are known to be allergic or hypersensitive to the IMP or any of its components
* Participants who have participated in any clinical trial within 60 days prior to signing the ICF or who have participated in more than 2 clinical trials within the year prior to signing the ICF
* Participants with difficulty swallowing
* Participants who answer "Yes" on the C-SSRS Suicidal Ideation Item 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) and whose most recent episode meeting criteria for this C-SSRS Item 4 occurred within the last 6 months, OR Subjects who answer "Yes" on the C-SSRS Suicidal Ideation Item 5 (Active Suicidal Ideation with Specific Plan and Intent) and whose most recent episode meeting criteria for this CSSRS Item 5 occurred within the last 6 months OR Subjects who answer "Yes" on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior) and whose most recent episode meeting criteria for any of these 5 C-SSRS Suicidal Behavior Items occurred in the last 2 years

Primary outcomes:
measure: Response Ratio (RRatio)
timeFrame: Baseline Period; Maintenance Phase Days 15 through 71
Secondary outcomes:
measure: Percentage Change From Baseline in Focal Onset Seizure Frequency Per Week Over the Maintenance Phase
timeFrame: Baseline Period; Maintenance Phase Days 15 through 71
measure: Percentage of Participants With 50 Percent (%) Responder Rate
timeFrame: Baseline Period; Maintenance Phase Days 15 through 71
measure: Percentage of Seizure-free Participants During the Maintenance Phase
timeFrame: Maintenance Phase Days 15 through 71
measure: Weekly Seizure Rate During the Maintenance Phase
timeFrame: Maintenance Phase Weeks 1, 2, 3, 4, 5, 6, 7, 8
measure: Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71
timeFrame: Maintenance Phase Days 15, 43, and 71
measure: Change From Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Maintenance Phase Days 15, 43, and 71
timeFrame: Baseline, Maintenance Phase Days 15, 43, and 71
measure: Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71
timeFrame: Baseline, Maintenance Phase Days 15, 43, and 71
measure: Change From Baseline in Quality of Life in Epilepsy-31 (QOLIE-31) Overall Score at Maintenance Phase Day 71
timeFrame: Baseline, Maintenance Phase Day 71
measure: Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71
timeFrame: Baseline, Maintenance Phase Day 71
measure: Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
measure: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs)
timeFrame: Baseline; From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
measure: Number of Participants With Clinically Significant Changes in Vital Sign Measurements
timeFrame: From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
measure: Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results
timeFrame: Baseline; From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
measure: Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS)
timeFrame: From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
measure: Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment
timeFrame: Maintenance Phase Day 71, Taper Phase Days 78, 85, and 92, and Safety Follow-up Days 99 and 120
measure: Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI)
timeFrame: From first dose of study drug until 30 days following last dose of study drug (up to Day 120)
measure: Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92
timeFrame: Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Little Rock, Arkansas
state: Arkansas
city: Downey
country: United States
facility: Downey, California
state: California
city: Loma Linda
country: United States
facility: Loma Linda, California
state: California
city: Valencia
country: United States
facility: Valencia, California
state: California
city: New Haven
country: United States
facility: New Haven, Connecticut
state: Connecticut
city: Altamonte Springs
country: United States
facility: Altamonte Springs, Florida
state: Florida
city: Gulf Breeze
country: United States
facility: Gulf Breeze, Florida
state: Florida
city: Homestead
country: United States
facility: Homestead, Florida
state: Florida
city: Jacksonville
country: United States
facility: Jacksonville, Florida
state: Florida
city: Miami Lakes
country: United States
facility: Miami Lakes, Florida
state: Florida
city: Miami
country: United States
facility: Miami, Florida
state: Florida
city: Orlando
country: United States
facility: Orlando, Florida
state: Florida
city: Port Charlotte
country: United States
facility: Port Charlotte, Florida
state: Florida
city: Port Orange
country: United States
facility: Port Orange, Florida
state: Florida
city: Tampa
country: United States
facility: Tampa, Florida
state: Florida
city: Suwanee
country: United States
facility: Suwanee, Georgia,
state: Georgia
city: Honolulu
country: United States
facility: Honolulu, Hawaii
state: Hawaii
city: Lexington
country: United States
facility: Lexington, Kentucky
state: Kentucky
city: Scarborough
country: United States
facility: Scarborough, Maine
state: Maine
city: Baltimore
country: United States
facility: Baltimore, Maryland
state: Maryland
city: Bethesda
country: United States
facility: Bethesda, Maryland
state: Maryland
city: Boston
country: United States
facility: Boston, Massachusetts
state: Massachusetts
city: Chesterfield
country: United States
facility: Chesterfield, Missouri
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis, Missouri
state: Missouri
city: Hackensack
country: United States
facility: Hackensack, New Jersey
state: New Jersey
city: Mineola
country: United States
facility: Mineola, New York
state: New York
city: New York
country: United States
facility: New York
state: New York
city: Rochester
country: United States
facility: Rochester, New York
state: New York
city: Syracuse
country: United States
facility: Syracuse, New York
state: New York
city: Columbus
country: United States
facility: Columbus, Ohio
state: Ohio
city: Toledo
country: United States
facility: Toledo, Ohio
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma City, Oklahoma
state: Oklahoma
city: Philadelphia
country: United States
facility: Philadelphia, Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Philadelphia, Pennsylvania
state: Pennsylvania
city: Charleston
country: United States
facility: Charleston, South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Nashville, Tennessee
state: Tennessee
city: Salt Lake City
country: United States
facility: Salt Lake City, Utah
state: Utah
city: Camperdown
country: Australia
facility: Camperdown, New South Wales
state: New South Wales
city: Randwick
country: Australia
facility: Randwick, New South Wales
state: New South Wales
city: Westmead
country: Australia
facility: Westmead, New South Wales
state: New South Wales
city: Herston
country: Australia
facility: Herston, Queensland
state: Queensland
city: South Brisbane
country: Australia
facility: South Brisbane, Queensland
state: Queensland
city: Fitzroy
country: Australia
facility: Fitzroy, Victoria
state: Victoria
city: Heidelberg
country: Australia
facility: Heidelberg, Victoria
state: Victoria
city: Melbourne
country: Australia
facility: Melbourne, Victoria
state: Victoria
city: Parkville
country: Australia
facility: Parkville, Victoria
state: Victoria
city: Gwangju
country: Korea, Republic of
facility: Gwangjin-gu, Seoul
state: Seoul
city: Irwon-dong
country: Korea, Republic of
facility: Irwon-Ro Gangnam-gu., Seoul
state: Seoul
city: Bydgoszcz
country: Poland
facility: Bydgoszcz, Kujawsko-Pomorskie
state: Kujawsko-Pomorskie
city: Łódź
country: Poland
facility: Lodz
state: Lodz
city: Kraków
country: Poland
facility: Kraków, Malopolskie
state: Malopolskie
city: Warszawa
country: Poland
facility: Warszawa, Mazowieckie
state: Mazowieckie
city: Gdańsk
country: Poland
facility: Gdańsk, Pomorskie
state: Pomorskie
city: Gdańsk
country: Poland
facility: Gdańsk, Pomorskie
state: Pomorskie
city: Wojnicz
country: Poland
facility: Wojnicz, Lskie
state: Wojnicz Lskie
city: Białystok
country: Poland
facility: Białystok
city: Lublin
country: Poland
facility: Lublin
city: Warszawa
country: Poland
facility: Warszawa
city: Kragujevac
country: Serbia
facility: Kragujevac, Sumadija
state: Sumadija
city: Kragujevac
country: Serbia
facility: Neurology Department, Kragujevac
state: Sumadija
city: Belgrade
country: Serbia
facility: Belgrade
city: Belgrade
country: Serbia
facility: Clinic of Neurology, Belgrade
city: Niš
country: Serbia
facility: Niš
city: Málaga
country: Spain
facility: Malaga,
state: Andalusia
city: Barcelona
country: Spain
facility: Barcelona, Catalunya
state: Catalonia
city: Terrassa
country: Spain
facility: Terrassa
state: Catalonia
city: Navarro
country: Spain
facility: Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Barcelona
city: Madrid
country: Spain
facility: Madrid
city: Madrid
country: Spain
facility: Madrid
city: Madrid
country: Spain
facility: Madrid
city: Sevilla
country: Spain
facility: Sevilla
city: Valencia
country: Spain
facility: Valencia
city: Úzhgorod
country: Ukraine
facility: Uzhgorod
state: Uzhgorod
city: Kyiv
country: Ukraine
facility: Kyiv
city: Lviv
country: Ukraine
facility: Lviv
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: Gurrell R, Iredale P, Evrard A, Duveau V, Ruggiero C, Roucard C. Pronounced antiseizure activity of the subtype-selective GABAA positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy. CNS Neurosci Ther. 2022 Nov;28(11):1875-1882. doi: 10.1111/cns.13927. Epub 2022 Aug 14.