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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04244175




Registration number
NCT04244175
Ethics application status
Date submitted
24/01/2020
Date registered
28/01/2020
Date last updated
2/08/2024

Titles & IDs
Public title
A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures
Scientific 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)
Secondary ID [1] 0 0
2019-002576-14
Secondary ID [2] 0 0
CVL-865-SZ-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Seizures 0 0
Condition category
Condition code
Neurological 0 0 0 0
Epilepsy
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - CVL-865
Treatment: Drugs - Placebo

Experimental: High Dose: CVL-865 25 mg - Participants will receive CVL-865 tablets orally twice daily (BID) up to the maximum dose of 25 milligrams (mg) until Day 92 during the treatment period.

Experimental: Low Dose: CVL-865 7.5 mg - Participants will receive CVL-865 tablets orally BID up to the maximum dose of 7.5 mg until Day 92 during the treatment period.

Placebo comparator: Placebo - Participants will receive a placebo matched to CVL-865 tablets orally BID until Day 92 during the treatment period.


Treatment: Drugs: 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.

Treatment: Drugs: Placebo
Participants will receive CVL-865 matched placebo tablet orally BID during the treatment period.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Response Ratio (RRatio)
Timepoint [1] 0 0
Day 71
Secondary outcome [1] 0 0
Change From Baseline in Focal Onset Seizure Frequency per Week over the Maintenance Phase
Timepoint [1] 0 0
Baseline up to Day 71
Secondary outcome [2] 0 0
Percentage of Participants with 50 Percent (%) Responder Rate
Timepoint [2] 0 0
Day 71
Secondary outcome [3] 0 0
Percentage of Seizure-free Participants
Timepoint [3] 0 0
Baseline up to Day 71
Secondary outcome [4] 0 0
Seizure Rate over Time
Timepoint [4] 0 0
Baseline up to Day 71
Secondary outcome [5] 0 0
Patient's Global Impression of Change (PGIC) Score at Days 15, 43 and 71
Timepoint [5] 0 0
Baseline, Day 15, 43 and 71
Secondary outcome [6] 0 0
Change from Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Day 15, 43 and 71
Timepoint [6] 0 0
Baseline, Day 15, 43 and 71
Secondary outcome [7] 0 0
Change From Baseline in Clinical Global Impression-Improvement Scale (CGI-I) Score at Day 15, 43 and 71
Timepoint [7] 0 0
Baseline, Day 15, 43 and 71
Secondary outcome [8] 0 0
Change from Baseline in Quality of Life in Epilepsy -31 (QOLIE-31) Overall Score at Day 71
Timepoint [8] 0 0
Baseline, Day 71
Secondary outcome [9] 0 0
Change from Baseline in Health Utilities Index (HUI) Utility Score at Day 71
Timepoint [9] 0 0
Baseline, Day 71
Secondary outcome [10] 0 0
Number of Participants with Clinically Significant Changes in Electrocardiogram (ECGs)
Timepoint [10] 0 0
Baseline to Day 92 or early termination
Secondary outcome [11] 0 0
Number of Participants with Clinically Significant Changes in Vital Sign Measurements
Timepoint [11] 0 0
Baseline to Day 92 or early termination (ET)
Secondary outcome [12] 0 0
Number of Participants with Clinically Significant Changes in Physical and Neurological Examination Results
Timepoint [12] 0 0
Baseline to Day 92 or early termination (ET)
Secondary outcome [13] 0 0
Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS)
Timepoint [13] 0 0
From first dose of study drug up to Day 120 (follow up period)
Secondary outcome [14] 0 0
Number of Participants with Positive Response to Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B)
Timepoint [14] 0 0
Day 71 up to Day 120
Secondary outcome [15] 0 0
Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Timepoint [15] 0 0
From first dose of study drug up to Day 120 (follow up period)
Secondary outcome [16] 0 0
Plasma Concentrations of CVL-865
Timepoint [16] 0 0
Day 15, Day 43, Day 71, Day 92 and/or early termination (ET)

Eligibility
Key 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)
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
27/01/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/05/2024
Sample size
Target
Accrual to date
Final
154
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 0 0
Camperdown, New South Wales - Camperdown
Recruitment hospital [2] 0 0
Randwick, New South Wales - Randwick
Recruitment hospital [3] 0 0
Westmead, New South Wales - Westmead
Recruitment hospital [4] 0 0
Herston, Queensland - Herston
Recruitment hospital [5] 0 0
South Brisbane, Queensland - South Brisbane
Recruitment hospital [6] 0 0
Fitzroy, Victoria - Fitzroy
Recruitment hospital [7] 0 0
Heidelberg, Victoria - Heidelberg
Recruitment hospital [8] 0 0
Melbourne, Victoria - Melbourne
Recruitment hospital [9] 0 0
Parkville, Victoria - Parkville
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2031 - Randwick
Recruitment postcode(s) [3] 0 0
2145 - Westmead
Recruitment postcode(s) [4] 0 0
4029 - Herston
Recruitment postcode(s) [5] 0 0
4101 - South Brisbane
Recruitment postcode(s) [6] 0 0
3065 - Fitzroy
Recruitment postcode(s) [7] 0 0
3084 - Heidelberg
Recruitment postcode(s) [8] 0 0
3004 - Melbourne
Recruitment postcode(s) [9] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arkansas
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Georgia
Country [6] 0 0
United States of America
State/province [6] 0 0
Hawaii
Country [7] 0 0
United States of America
State/province [7] 0 0
Kentucky
Country [8] 0 0
United States of America
State/province [8] 0 0
Maine
Country [9] 0 0
United States of America
State/province [9] 0 0
Maryland
Country [10] 0 0
United States of America
State/province [10] 0 0
Massachusetts
Country [11] 0 0
United States of America
State/province [11] 0 0
Missouri
Country [12] 0 0
United States of America
State/province [12] 0 0
New Jersey
Country [13] 0 0
United States of America
State/province [13] 0 0
New York
Country [14] 0 0
United States of America
State/province [14] 0 0
Ohio
Country [15] 0 0
United States of America
State/province [15] 0 0
Oklahoma
Country [16] 0 0
United States of America
State/province [16] 0 0
Pennsylvania
Country [17] 0 0
United States of America
State/province [17] 0 0
South Carolina
Country [18] 0 0
United States of America
State/province [18] 0 0
Tennessee
Country [19] 0 0
United States of America
State/province [19] 0 0
Utah
Country [20] 0 0
Korea, Republic of
State/province [20] 0 0
Seoul
Country [21] 0 0
Poland
State/province [21] 0 0
Kujawsko-Pomorskie
Country [22] 0 0
Poland
State/province [22] 0 0
Lodz
Country [23] 0 0
Poland
State/province [23] 0 0
Malopolskie
Country [24] 0 0
Poland
State/province [24] 0 0
Mazowieckie
Country [25] 0 0
Poland
State/province [25] 0 0
Pomorskie
Country [26] 0 0
Poland
State/province [26] 0 0
Wojnicz Lskie
Country [27] 0 0
Poland
State/province [27] 0 0
Bialystok
Country [28] 0 0
Poland
State/province [28] 0 0
Lublin
Country [29] 0 0
Poland
State/province [29] 0 0
Warszawa
Country [30] 0 0
Serbia
State/province [30] 0 0
Sumadija
Country [31] 0 0
Serbia
State/province [31] 0 0
Belgrade
Country [32] 0 0
Serbia
State/province [32] 0 0
Niš
Country [33] 0 0
Spain
State/province [33] 0 0
Andalusia
Country [34] 0 0
Spain
State/province [34] 0 0
Catalonia
Country [35] 0 0
Spain
State/province [35] 0 0
Navarra
Country [36] 0 0
Spain
State/province [36] 0 0
Barcelona
Country [37] 0 0
Spain
State/province [37] 0 0
Madrid
Country [38] 0 0
Spain
State/province [38] 0 0
Sevilla
Country [39] 0 0
Spain
State/province [39] 0 0
Valencia
Country [40] 0 0
Ukraine
State/province [40] 0 0
Uzhgorod
Country [41] 0 0
Ukraine
State/province [41] 0 0
Kyiv
Country [42] 0 0
Ukraine
State/province [42] 0 0
Lviv

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Cerevel Therapeutics, LLC
Address
Country

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/study/NCT04244175
Trial related presentations / publications
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.
Public notes

Contacts
Principal investigator
Name 0 0
Eliza Hueda, MD
Address 0 0
Cerevel Therapeutics, LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04244175