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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04244175
Recruitment Status : Recruiting
First Posted : January 28, 2020
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
Cerevel Therapeutics, LLC

Tracking Information
First Submitted Date  ICMJE January 24, 2020
First Posted Date  ICMJE January 28, 2020
Last Update Posted Date November 17, 2020
Actual Study Start Date  ICMJE January 27, 2020
Estimated Primary Completion Date March 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
Response Ratio (RRatio) [ Time Frame: Day 71 ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2020)
  • Change From Baseline in Focal Onset Seizure Frequency per Week over the Maintenance Phase [ Time Frame: Baseline up to Day 71 ]
    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.
  • Percentage of Participants with 50 Percent (%) Responder Rate [ Time Frame: Day 71 ]
    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.
  • Percentage of Seizure-free Participants [ Time Frame: Baseline up to Day 71 ]
    Seizure freedom is defined as the absence of all seizure regardless of seizure type.
  • Seizure Rate over Time [ Time Frame: Baseline up to Day 71 ]
    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.
  • Patient's Global Impression of Change (PGIC) Score at Days 15, 43 and 71 [ Time Frame: Baseline, Day 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.
  • Change from Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Day 15, 43 and 71 [ Time Frame: Baseline, 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.
  • Change From Baseline in Clinical Global Impression-Improvement Scale (CGI-I) Score at Day 15, 43 and 71 [ Time Frame: Baseline, 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.
  • Change from Baseline in Quality of Life in Epilepsy -31 (QOLIE-31) Overall Score at Day 71 [ Time Frame: Baseline, 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.
  • Change from Baseline in Health Utilities Index (HUI) Utility Score at Day 71 [ Time Frame: Baseline, 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.
  • Number of Participants with Clinically Significant Changes in Electrocardiogram (ECGs) [ Time Frame: Baseline to Day 92 or early termination ]
    12-lead ECGs recordings will be obtained after the participant has been supine and at rest for at least 5 minutes.
  • Number of Participants with Clinically Significant Changes in Vital Sign Measurements [ Time Frame: Baseline to Day 92 or early termination (ET) ]
    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.
  • Number of Participants with Clinically Significant Changes in Physical and Neurological Examination Results [ Time Frame: Baseline to Day 92 or early termination (ET) ]
    Number of participants with clinically significant changes in physical and neurological examination results will be assessed.
  • Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) [ Time Frame: From first dose of study drug up to Day 120 (follow up period) ]
    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).
  • Number of Participants with Positive Response to Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) [ Time Frame: Day 71 up to Day 120 ]
    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.
  • Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) [ Time Frame: From first dose of study drug up to Day 120 (follow up period) ]
    TEAEs will include abuse-related AEs and AEs related to medication handling irregularities (MHIs). Number of Participants With TEAEs and TESAEs will be assessed.
  • Plasma Concentrations of CVL-865 [ Time Frame: Day 15, Day 43, Day 71, Day 92 and/or early termination (ET) ]
    Plasma concentration of CVL-865 at Day 15, Day 43, Day 71, Day 92 and/or early termination (ET) will be assessed.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
  • Percentage of Participants with 50% Responder Rate [ Time Frame: Day 71 ]
    The 50% 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.
  • Focal Onset Seizure Frequency per Week over the Maintenance Phase [ Time Frame: Baseline up to Day 71 ]
    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.
  • Percentage of Seizure-free Participants [ Time Frame: Baseline up to follow up period (Day 120) ]
    Seizure freedom is defined as the absence of all seizure regardless of seizure type.
  • Seizure Rate over Time [ Time Frame: Baseline up to follow up period (Day 120) ]
    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.
  • Patient's Global Impression of Change (PGIC) Score at Days 15, 43 and 71 [ Time Frame: Baseline, Day 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. Participant's rate their change as ''very much improved,'' ''much improved,'' ''minimally improved,'' ''no change,'' ''minimally worse,'' ''much worse,'' or ''very much worse.''
  • Change from Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Day 15, 43 and 71 [ Time Frame: Baseline, 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.
  • Change From Baseline in Clinical Global Impression-Improvement Scale (CGI-I) Score at Day 15, 43 and 71 [ Time Frame: Baseline, 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.
  • Change from Baseline in Quality of Life in Epilepsy -31 (QOLIE-31) Overall Score at Day 71 [ Time Frame: Baseline, 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.
  • Change from Baseline in Health Utilities Index (HUI) Utility Score at Day 71 [ Time Frame: Baseline, 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.
  • Number of Participants with Clinically Significant Changes in Electrocardiogram (ECGs) [ Time Frame: Baseline to Day 92 or early termination ]
    12-lead ECGs recordings will be obtained after the participant has been supine and at rest for at least 5 minutes.
  • Number of Participants with Clinically Significant Changes in Vital Sign Measurements [ Time Frame: Baseline to Day 92 or early termination (ET) ]
    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.
  • Number of Participants with Clinically Significant Changes in Physical and Neurological Examination Results [ Time Frame: Baseline to Day 92 or early termination (ET) ]
    Number of participants with clinically significant changes in physical and neurological examination results will be assessed.
  • Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) [ Time Frame: From first dose of study drug up to Day 120 (follow up period) ]
    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).
  • Number of Participants with Positive Response to Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) [ Time Frame: Day 71 up to Day 120 ]
    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.
  • Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) [ Time Frame: From first dose of study drug up to Day 120 (follow up period) ]
    TEAEs will include abuse-related AEs and AEs related to medication handling irregularities (MHIs). Number of Participants With TEAEs and TESAEs will be assessed.
  • Plasma Concentrations of CVL-865 [ Time Frame: Day 15, Day 43, Day 71, Day 92 or early termination (ET) ]
    Plasma concentration of CVL-865 at Day 15, Day 43, Day 71, Day 92 or early termination (ET) will be assessed.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures
Official Title  ICMJE 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)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Seizures
Intervention  ICMJE
  • 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.
  • Drug: Placebo
    Participants will receive CVL-865 matched placebo tablet orally BID during the treatment period.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: CVL-865
  • 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.
    Intervention: Drug: CVL-865
  • Placebo Comparator: Placebo
    Participants will receive a placebo matched to CVL-865 tablets orally BID until Day 92 during the treatment period.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2020)
150
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 1, 2022
Estimated Primary Completion Date March 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Australia,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04244175
Other Study ID Numbers  ICMJE CVL-865-SZ-001
2019-002576-14 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Cerevel Therapeutics, LLC
Study Sponsor  ICMJE Cerevel Therapeutics, LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Julie Jordan, MD Cerevel Therapeutics, LLC
PRS Account Cerevel Therapeutics, LLC
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP