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

Sponsor

Cerevel Therapeutics, LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04244175

Collaborator

(none)

150

Enrollment

Locations

Arms

33.1

Anticipated Duration (Months)

2.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Seizures	Drug: CVL-865 Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Jan 27, 2020

Anticipated Primary Completion Date :

Oct 1, 2022

Anticipated Study Completion Date :

Nov 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
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.	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.
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.	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 Comparator: Placebo Participants will receive a placebo matched to CVL-865 tablets orally BID until Day 92 during the treatment period.	Drug: Placebo Participants will receive CVL-865 matched placebo tablet orally BID during the treatment period.

Arm

Intervention/Treatment

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.

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.

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.

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 Comparator: Placebo

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

Drug: Placebo

Participants will receive CVL-865 matched placebo tablet orally BID during the treatment period.

Outcome Measures

Primary Outcome Measures

Response Ratio (RRatio) [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.

Secondary Outcome Measures

Change From Baseline in Focal Onset Seizure Frequency per Week over the Maintenance Phase [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 [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 [Baseline up to Day 71]
Seizure freedom is defined as the absence of all seizure regardless of seizure type.
Seizure Rate over Time [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 [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 [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 [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 [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 [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) [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 [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 [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) [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) [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) [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Los Angeles, California	Los Angeles	California	United States	90048
2	Colorado Springs, Colorado	Colorado Springs	Colorado	United States	80907
3	New Haven, Connecticut	New Haven	Connecticut	United States	06520
4	Gulf Breeze, Florida	Gulf Breeze	Florida	United States	32561-4458
5	Jacksonville, Florida	Jacksonville	Florida	United States	32224
6	Miami, Florida	Miami	Florida	United States	33136
7	Miami, Florida	Miami	Florida	United States	33156
8	Orlando, Florida	Orlando	Florida	United States	32806
9	Port Charlotte, Florida	Port Charlotte	Florida	United States	33952
10	Tallahassee, Florida	Tallahassee	Florida	United States	32308
11	Tampa, Florida	Tampa	Florida	United States	33606
12	Atlanta, Georgia	Atlanta	Georgia	United States	30327
13	Suwanee, Georgia,	Suwanee	Georgia	United States	30024
14	Honolulu, Hawaii	Honolulu	Hawaii	United States	96817
15	Boise, Idaho	Boise	Idaho	United States	83702
16	Urbana, Illinois	Urbana	Illinois	United States	61801
17	Winfield, Illinois	Winfield	Illinois	United States	60190
18	Lexington, Kentucky	Lexington	Kentucky	United States	40504
19	Scarborough, Maine	Scarborough	Maine	United States	04074
20	Baltimore, Maryland	Baltimore	Maryland	United States	21287
21	Bethesda, Maryland	Bethesda	Maryland	United States	20817
22	Boston, Massachusetts	Boston	Massachusetts	United States	02114
23	Roseville, Minnesota	Roseville	Minnesota	United States	55113
24	Saint Louis, Missouri	Saint Louis	Missouri	United States	63110
25	Hackensack, New Jersey	Hackensack	New Jersey	United States	07601
26	Bronx, New York	Bronx	New York	United States	10467
27	Mineola, New York	Mineola	New York	United States	11501
28	New York	New York	New York	United States	10016
29	New York	New York	New York	United States	10021
30	Rochester, New York	Rochester	New York	United States	14642
31	Syracuse, New York	Syracuse	New York	United States	13210
32	Columbus, Ohio	Columbus	Ohio	United States	43221
33	Toledo, Ohio	Toledo	Ohio	United States	43614
34	Oklahoma City, Oklahoma	Oklahoma City	Oklahoma	United States	73112
35	Philadelphia, Pennsylvania	Philadelphia	Pennsylvania	United States	19104
36	Philadelphia, Pennsylvania	Philadelphia	Pennsylvania	United States	19107
37	Charleston, South Carolina	Charleston	South Carolina	United States	29425
38	Cordova, Tennessee	Cordova	Tennessee	United States	38018
39	Nashville, Tennessee	Nashville	Tennessee	United States	37232
40	Salt Lake City, Utah	Salt Lake City	Utah	United States	84108
41	Camperdown, New South Wales	Camperdown	New South Wales	Australia	2050
42	Randwick, New South Wales	Randwick	New South Wales	Australia	2031
43	Westmead, New South Wales	Westmead	New South Wales	Australia	2145
44	Herston, Queensland	Herston	Queensland	Australia	4029
45	South Brisbane, Queensland	South Brisbane	Queensland	Australia	4101
46	Bedford Park, SA	Bedford Park	South Australia	Australia	5042
47	Box Hill, Victoria	Box Hill	Victoria	Australia	3128
48	Fitzroy, Victoria	Fitzroy	Victoria	Australia	3065
49	Heidelberg, Victoria	Heidelberg	Victoria	Australia	3084
50	Melbourne, Victoria	Melbourne	Victoria	Australia	3004
51	Parkville, Victoria	Parkville	Victoria	Australia	3050
52	Wojnicz, Lskie	Wojnicz	Wojnicz Lskie	Poland	40-650
53	Malaga,	Málaga	Andalusia	Spain	29010
54	Barcelona, Catalunya	Barcelona	Catalonia	Spain	08003
55	Terrassa	Terrassa	Catalonia	Spain	08222
56	Navarra	Navarro	Navarra	Spain	31008
57	Barcelona	Barcelona		Spain	8035
58	Madrid	Madrid		Spain	28034
59	Madrid	Madrid		Spain	28040
60	Sevilla	Sevilla		Spain	41013
61	Valencia	Valencia		Spain	46026