A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures

Seizures Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04244175
• Other study ID #: CVL-865-SZ-001
• Secondary ID: 2019-002576-14
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 27, 2020
• Est. completion date: July 2024

Study information

• Verified date: May 2024
• Source: Cerevel Therapeutics, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the efficacy, safety, and tolerability profile of CVL-865 as adjunctive treatment in participants with drug-resistant focal onset seizures.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 154
• Est. completion date: July 2024
• Est. primary completion date: May 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Seizures

Intervention

Drug:
• CVL-865
Participants will receive CVL-865 tablets orally BID up to the maximum dose of 7.5 mg BID or 25 mg BID during the treatment period.
• Placebo
Participants will receive CVL-865 matched placebo tablet orally BID during the treatment period.

Locations

Country	Name	City	State
Australia	Camperdown, New South Wales	Camperdown	New South Wales
Australia	Fitzroy, Victoria	Fitzroy	Victoria
Australia	Heidelberg, Victoria	Heidelberg	Victoria
Australia	Herston, Queensland	Herston	Queensland
Australia	Melbourne, Victoria	Melbourne	Victoria
Australia	Parkville, Victoria	Parkville	Victoria
Australia	Randwick, New South Wales	Randwick	New South Wales
Australia	South Brisbane, Queensland	South Brisbane	Queensland
Australia	Westmead, New South Wales	Westmead	New South Wales
Poland	Bialystok	Bialystok
Poland	Bydgoszcz, Kujawsko-Pomorskie	Bydgoszcz	Kujawsko-Pomorskie
Poland	Gdansk, Pomorskie	Gdansk	Pomorskie
Poland	Gdansk, Pomorskie	Gdansk	Pomorskie
Poland	Kraków, Malopolskie	Kraków	Malopolskie
Poland	Lodz	Lódz	Lodz
Poland	Lublin	Lublin
Poland	Warszawa	Warszawa
Poland	Warszawa, Mazowieckie	Warszawa	Mazowieckie
Poland	Wojnicz, Lskie	Wojnicz	Wojnicz Lskie
Serbia	Belgrade	Belgrade
Serbia	Clinic of Neurology, Belgrade	Belgrade
Serbia	Kragujevac, Sumadija	Kragujevac	Sumadija
Serbia	Neurology Department, Kragujevac	Kragujevac	Sumadija
Serbia	Niš	Niš
Spain	Barcelona	Barcelona
Spain	Barcelona, Catalunya	Barcelona	Catalonia
Spain	Madrid	Madrid
Spain	Madrid	Madrid
Spain	Madrid	Madrid
Spain	Malaga,	Málaga	Andalusia
Spain	Navarra	Navarro	Navarra
Spain	Sevilla	Sevilla
Spain	Terrassa	Terrassa	Catalonia
Spain	Valencia	Valencia
Ukraine	Kyiv	Kyiv
Ukraine	Lviv	Lviv
Ukraine	Uzhgorod	Úzhgorod	Uzhgorod
United States	Altamonte Springs, Florida	Altamonte Springs	Florida
United States	Baltimore, Maryland	Baltimore	Maryland
United States	Bethesda, Maryland	Bethesda	Maryland
United States	Boston, Massachusetts	Boston	Massachusetts
United States	Charleston, South Carolina	Charleston	South Carolina
United States	Chesterfield, Missouri	Chesterfield	Missouri
United States	Columbus, Ohio	Columbus	Ohio
United States	Downey, California	Downey	California
United States	Gulf Breeze, Florida	Gulf Breeze	Florida
United States	Hackensack, New Jersey	Hackensack	New Jersey
United States	Homestead, Florida	Homestead	Florida
United States	Honolulu, Hawaii	Honolulu	Hawaii
United States	Jacksonville, Florida	Jacksonville	Florida
United States	Lexington, Kentucky	Lexington	Kentucky
United States	Little Rock, Arkansas	Little Rock	Arkansas
United States	Loma Linda, California	Loma Linda	California
United States	Miami, Florida	Miami	Florida
United States	Miami Lakes, Florida	Miami Lakes	Florida
United States	Mineola, New York	Mineola	New York
United States	Nashville, Tennessee	Nashville	Tennessee
United States	New Haven, Connecticut	New Haven	Connecticut
United States	New York	New York	New York
United States	Oklahoma City, Oklahoma	Oklahoma City	Oklahoma
United States	Orlando, Florida	Orlando	Florida
United States	Philadelphia, Pennsylvania	Philadelphia	Pennsylvania
United States	Philadelphia, Pennsylvania	Philadelphia	Pennsylvania
United States	Port Charlotte, Florida	Port Charlotte	Florida
United States	Port Orange, Florida	Port Orange	Florida
United States	Rochester, New York	Rochester	New York
United States	Saint Louis, Missouri	Saint Louis	Missouri
United States	Salt Lake City, Utah	Salt Lake City	Utah
United States	Scarborough, Maine	Scarborough	Maine
United States	Suwanee, Georgia,	Suwanee	Georgia
United States	Syracuse, New York	Syracuse	New York
United States	Tampa, Florida	Tampa	Florida
United States	Toledo, Ohio	Toledo	Ohio
United States	Valencia, California	Valencia	California

Sponsors (1)

Lead Sponsor	Collaborator
Cerevel Therapeutics, LLC

Countries where clinical trial is conducted

United States,  Australia,  Poland,  Serbia,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Response Ratio (RRatio)	Response Ratio (RRatio), calculated as RRatio=(T-B)/(T+B) ×100, where T represents the focal onset seizure frequency rate per week in the Maintenance Phase and B represents the focal onset seizure frequency rate per week in the Baseline Period.	Day 71
Secondary	Change From Baseline in Focal Onset Seizure Frequency per Week over the Maintenance Phase	Seizure frequency is defined as the total number of focal onset seizures over the treatment period of interest divided by the total number of days with no missing seizure counts in the corresponding period multiplied by 7.	Baseline up to Day 71
Secondary	Percentage of Participants with 50 Percent (%) Responder Rate	Defined as the percent of participants with at least a 50% reduction in the Maintenance Phase focal onset seizure frequency rate relative to the Baseline Period.	Day 71
Secondary	Percentage of Seizure-free Participants	Seizure freedom is defined as the absence of all seizure regardless of seizure type.	Baseline up to Day 71
Secondary	Seizure Rate over Time	Seizure frequency is defined as the total number of focal onset seizures over the treatment period of interest divided by the total number of days with no missing seizure counts in the corresponding period multiplied by 7.	Baseline up to Day 71
Secondary	Patient's Global Impression of Change (PGIC) Score at Days 15, 43 and 71	The self-report measure Patient's Global Impression of Change (PGIC) reflects a participant's belief about the efficacy of treatment. It is a 7-point scale depicting a participant's rating of overall improvement where 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse and 7 = very much worse.	Baseline, Day 15, 43 and 71
Secondary	Change from Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Day 15, 43 and 71	The CGI-S is an observer-rated scale that will be used to measure symptom severity. It is a 7-point scale depicting a participants rating of overall improvement. Participants rate their change as 0 = not assessed; 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.	Baseline, Day 15, 43 and 71
Secondary	Change From Baseline in Clinical Global Impression-Improvement Scale (CGI-I) Score at Day 15, 43 and 71	The CGI-I is an observer-rated scale that will be used to measure the participant's symptom severity compared with before initiation of treatment with IMP. It is a 7-point scale depicting a participant's change from baseline in symptom severity using the following response choices: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.	Baseline, Day 15, 43 and 71
Secondary	Change from Baseline in Quality of Life in Epilepsy -31 (QOLIE-31) Overall Score at Day 71	The Quality of Life in Epilepsy - 31 (QOLIE-31) contains 7 multi-item scales that tap the following health concepts: emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, medication effects, and overall quality of life. A QOLIE-31 overall score is obtained using a weighted average of the multi-item scale scores. The QOLIE-31 also includes a single item that assessed overall health. The QoLIE-31 score range is from 0 to 100 with a higher score indicating a better outcome for quality of life.	Baseline, Day 71
Secondary	Change from Baseline in Health Utilities Index (HUI) Utility Score at Day 71	The Health Utilities Index (HUI) is a rating scale used to measure general health status and health-related quality of life. In HUI, utility values range from -0.03 and -0.36 for the HUI-2 and HUI-3, respectively, to 1.00. A health utility value of 1.00 indicates perfect health while a score of 0.00 indicates death.	Baseline, Day 71
Secondary	Number of Participants with Clinically Significant Changes in Electrocardiogram (ECGs)	12-lead ECGs recordings will be obtained after the participant has been supine and at rest for at least 5 minutes.	Baseline to Day 92 or early termination
Secondary	Number of Participants with Clinically Significant Changes in Vital Sign Measurements	Vital signs will be measured with the participant in a sitting/semi-recumbent position after 5 minutes rest and will include temperature, systolic and diastolic blood pressure, and heart rate.	Baseline to Day 92 or early termination (ET)
Secondary	Number of Participants with Clinically Significant Changes in Physical and Neurological Examination Results	Number of participants with clinically significant changes in physical and neurological examination results will be assessed.	Baseline to Day 92 or early termination (ET)
Secondary	Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS)	The C-SSRS rates an individual's degree of suicidal ideation (SI) on a scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent." The scale identifies SI severity and intensity, which may be indicative of an individual's intent to commit suicide. C-SSRS SI severity subscale ranges from 0 (no SI) to 5 (active SI with plan and intent).	From first dose of study drug up to Day 120 (follow up period)
Secondary	Number of Participants with Positive Response to Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B)	The modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) is a sensitive instrument to measure withdrawal under conditions where there is a taper of medication (rather than abrupt discontinuation). It consists of 17-items that monitor the type and severity of BZD withdrawal symptoms such as irritability, fatigue, appetite, and sleeplessness. The total score ranges from 1 to 68 with higher scores indicating more severe withdrawal.	Day 71 up to Day 120
Secondary	Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	TEAEs will include abuse-related AEs and AEs related to medication handling irregularities (MHIs). Number of Participants With TEAEs and TESAEs will be assessed.	From first dose of study drug up to Day 120 (follow up period)
Secondary	Plasma Concentrations of CVL-865	Plasma concentration of CVL-865 at Day 15, Day 43, Day 71, Day 92 and/or early termination (ET) will be assessed.	Day 15, Day 43, Day 71, Day 92 and/or early termination (ET)