A Trial of the Efficacy and Safety of CVL-865 as Adjuncti... | NCT04244175

NCT04244175

ID	Type	Description	Link
2019-002576-14	EudraCT Number

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.	Drug: Placebo
CVL-865 7.5 mg BID	Experimental	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.	Drug: CVL-865
CVL-865 25 mg BID	Experimental	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.	Drug: CVL-865

Name	Type	Description	Arm Group Labels	Other Names
Placebo	Drug	Participants received CVL-865 matched placebo tablets orally twice a day (BID) during the Treatment Period.	Placebo

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Response Ratio (RRatio)	Response Ratio (RRatio) is 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. The Response Ratio ranges between -100 and 100; negative values indicate reduction in seizure rate and positive values indicate increase in seizure rate during treatment.	Baseline Period; Maintenance Phase Days 15 through 71

Secondary Outcomes

Measure	Description	Time Frame
Percentage 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 Period; Maintenance Phase Days 15 through 71

Eligibility Module

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

Contacts/Locations Module

Name	Affiliation	Role
ABBVIE INC.	AbbVie	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Little Rock, Arkansas		Little Rock	Arkansas	72205	United States
Downey, California

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
35965432	Derived	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.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
FG001	CVL-865 7.5 mg BID

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 30, 2020	May 6, 2025

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Intent-to-Treat (ITT) population: all randomized participants

Arm/Group Information

ID	Title	Description
BG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
BG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
BG002	CVL-865 25 mg BID	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
BG003	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title	Denominators	Categories
	ParticipantsBG00051 ParticipantsBG00151 ParticipantsBG00252 ParticipantsBG003

Sex: Female, Male

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG00051 ParticipantsBG00151 ParticipantsBG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title	Denominators	Categories
	ParticipantsBG00051 ParticipantsBG00151 ParticipantsBG002

Race/Ethnicity, Customized

Count of Participants

Participants

Title	Denominators	Categories
American Indian or Alaska Native	ParticipantsBG00051 ParticipantsBG00151 ParticipantsBG002

Duration of Epilepsy

Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)

Mean

Standard Deviation

years

Title	Denominators	Categories
	ParticipantsBG00051 ParticipantsBG00150 ParticipantsBG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Response Ratio (RRatio)

Response Ratio (RRatio) is 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. The Response Ratio ranges between -100 and 100; negative values indicate reduction in seizure rate and positive values indicate increase in seizure rate during treatment.

Modified intent-to-treat (mITT): All randomized participants who receive at least 1 dose of investigational medicinal product and have both Baseline seizure frequency recorded in the eDiary with entry compliance ≥20% and at least 1 post-Baseline entry in the seizure diary during the Maintenance Phase. Data are presented for participants with a non-missing value.

Posted

Mean

Standard Deviation

RRatio

Baseline Period; Maintenance Phase Days 15 through 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002	CVL-865 25 mg BID	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG003	CVL-865 7.5 mg BID / 25 mg BID	7.5 mg BID: CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. 25 mg BID: CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Units	Counts
Participants	OG00050 OG00146 OG00247 OG003

Title

Denominators

Categories

Title	Measurements
	OG000-24.06± 33.441 OG001-22.45± 26.393 OG002-25.90± 33.428 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002	CVL-865 25 mg BID vs Placebo	ANCOVA		=0.986		LS Mean Difference	0.11			2-Sided	90	-10.38	10.61			CVL-865 25 mg BID - Placebo		Superiority	RRatio was analyzed using an analysis of covariance (ANCOVA) model including treatment and the Baseline seizure frequency per week as a covariate.

Secondary

Percentage 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.

Posted

Number

Percentage change from Baseline

Baseline Period; Maintenance Phase Days 15 through 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Percentage of Participants With 50 Percent (%) Responder Rate

The 50% responder rate is defined as the percentage of participants with at least a 50% reduction in focal onset seizure frequency rate in the Maintenance Phase compared to the Baseline Period.

Posted

Number

percentage of participants

Baseline Period; Maintenance Phase Days 15 through 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002

Secondary

Percentage of Seizure-free Participants During the Maintenance Phase

Seizure freedom is defined as no seizures during the Maintenance Phase.

Posted

Number

percentage of participants

Maintenance Phase Days 15 through 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002	CVL-865 25 mg BID

Secondary

Weekly Seizure Rate During the Maintenance Phase

Posted

Mean

Standard Deviation

Seizures/week

Maintenance Phase Weeks 1, 2, 3, 4, 5, 6, 7, 8

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002

Secondary

Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71

The self-report measure Patient's Global Impression of Change (PGI-C) 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. Lower scores indicate improvement.

Posted

Mean

Standard Deviation

units on a scale

Maintenance Phase Days 15, 43, and 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Change From Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Maintenance Phase Days 15, 43, and 71

The CGI-S is an observer-rated scale that was 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. Negative changes from Baseline indicate improvement.

Posted

Mean

Standard Deviation

units on a scale

Baseline, Maintenance Phase Days 15, 43, and 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71

The CGI-I is an observer-rated scale that was used to measure the participant's symptom severity compared with before initiation of treatment with the investigational medicinal product (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. Lower scores indicate improvement.

Posted

Mean

Standard Deviation

units on a scale

Baseline, Maintenance Phase Days 15, 43, and 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Change From Baseline in Quality of Life in Epilepsy-31 (QOLIE-31) Overall Score at Maintenance Phase Day 71

The Quality of Life in Epilepsy-31 (QOLIE-31) contains 7 multi-item scales that cover 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. Positive changes from Baseline indicate improvement.

Posted

Mean

Standard Deviation

units on a scale

Baseline, Maintenance Phase Day 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase 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. Negative changes from Baseline indicate improvement.

Modified intent-to-treat (mITT): All randomized participants who receive at least 1 dose of investigational medicinal product and have both Baseline seizure frequency recorded in the eDiary with entry compliance ≥20% and at least 1 post Baseline entry in the seizure diary during the Maintenance Phase. Data are presented for participants with a non-missing value.

Posted

Mean

Standard Deviation

units on a scale

Baseline, Maintenance Phase Day 71

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.

Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)

Posted

Count of Participants

Participants

From first dose of study drug until 30 days following last dose of study drug (up to Day 120)

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID

Secondary

Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs)

12-lead electrocardiogram (ECG) recordings were obtained after the participant had been supine and at rest for at least 5 minutes.

Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)

Posted

Count of Participants

Participants

Baseline; From first dose of study drug until 30 days following last dose of study drug (up to Day 120)

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002	CVL-865 25 mg BID	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Number of Participants With Clinically Significant Changes in Vital Sign Measurements

Vital signs were measured with the participant in a sitting/semi-recumbent position after 5 minutes rest and included temperature, systolic and diastolic blood pressure, respiratory rate, and heart rate.

Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)

Posted

Count of Participants

Participants

From first dose of study drug until 30 days following last dose of study drug (up to Day 120)

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002	CVL-865 25 mg BID	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results

The number of participants with clinically significant changes in physical and neurological examination results was documented.

Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)

Posted

Count of Participants

Participants

Baseline; From first dose of study drug until 30 days following last dose of study drug (up to Day 120)

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002	CVL-865 25 mg BID	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

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).

Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)

Posted

Count of Participants

Participants

From first dose of study drug until 30 days following last dose of study drug (up to Day 120)

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002

Secondary

Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment

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. Baseline is defined as the last on-treatment assessment on Day 71. Negative changes from Baseline indicate a reduction in withdrawal symptoms.

Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP). Data are presented for participants with a non-missing value.

Posted

Mean

Standard Deviation

units on a scale

Maintenance Phase Day 71, Taper Phase Days 78, 85, and 92, and Safety Follow-up Days 99 and 120

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI)

Adverse events potentially related to abuse or dependence of the investigational medicinal product (IMP) were documented.

Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)

Posted

Count of Participants

Participants

From first dose of study drug until 30 days following last dose of study drug (up to Day 120)

ID	Title	Description
OG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.
OG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG002	CVL-865 25 mg BID	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Secondary

Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92

Plasma concentration of CVL-865 was measured on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92.

All randomized participants who receive at least 1 dose of the investigational medicinal product (IMP) and have at least 1 measurable CVL-865 concentration. Data are presented for participants with a non-missing value.

Posted

Mean

Standard Deviation

ng/mL

Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92

ID	Title	Description
OG000	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.
OG001	CVL-865 25 mg BID	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Participants received a placebo matched to CVL-865 tablets orally twice a day (BID) during the 2-week Titration Phase, the 8-week Maintenance Phase, and the 3-week Taper Phase.	51	1	51	24	51
EG001	CVL-865 7.5 mg BID	CVL-865 tablets were administered orally as 2.5 mg twice a day (BID) for 1 week followed by 5 mg BID for another week during the Titration Phase, and then 7.5 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.	51	4	51	26	51
EG002	CVL-865 25 mg BID	CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.	52	2	52	38	52

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
THROMBOCYTOPENIA	Blood and lymphatic system disorders	MedDRA 27.0	Systematic Assessment	EG0001 events1 affected51 at risk EG0010 events0 affected51 at risk EG0020 events0 affected52 at risk
CHOLECYSTITIS	Hepatobiliary disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0010 events0 affected51 at risk EG0021 events1 affected52 at risk
SKIN LACERATION	Injury, poisoning and procedural complications	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0011 events1 affected51 at risk EG0020 events0 affected52 at risk
GENERALISED TONIC-CLONIC SEIZURE	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0010 events0 affected51 at risk EG0021 events1 affected52 at risk
MYOCLONUS	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0011 events1 affected51 at risk EG0020 events0 affected52 at risk
SUICIDAL IDEATION	Psychiatric disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0011 events1 affected51 at risk EG0020 events0 affected52 at risk
PERIPHERAL ARTERY OCCLUSION	Vascular disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0011 events1 affected51 at risk EG0020 events0 affected52 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
NEUTROPENIA	Blood and lymphatic system disorders	MedDRA 27.0	Systematic Assessment	EG0001 events1 affected51 at risk EG0013 events3 affected51 at risk EG0025 events5 affected52 at risk
THROMBOCYTOPENIA	Blood and lymphatic system disorders	MedDRA 27.0	Systematic Assessment	EG0004 events3 affected51 at risk EG0013 events3 affected51 at risk EG0024 events4 affected52 at risk
VISION BLURRED	Eye disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0012 events2 affected51 at risk EG0020 events0 affected52 at risk
DENTAL CARIES	Gastrointestinal disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0010 events0 affected51 at risk EG0023 events2 affected52 at risk
NAUSEA	Gastrointestinal disorders	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0010 events0 affected51 at risk EG0021 events1 affected52 at risk
ASTHENIA	General disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0012 events2 affected51 at risk EG0023 events2 affected52 at risk
FATIGUE	General disorders	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0016 events3 affected51 at risk EG0026 events6 affected52 at risk
COVID-19	Infections and infestations	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0010 events0 affected51 at risk EG0020 events0 affected52 at risk
FALL	Injury, poisoning and procedural complications	MedDRA 27.0	Systematic Assessment	EG0008 events5 affected51 at risk EG0013 events3 affected51 at risk EG0021 events1 affected52 at risk
HEAD INJURY	Injury, poisoning and procedural complications	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0012 events2 affected51 at risk EG0020 events0 affected52 at risk
ALANINE AMINOTRANSFERASE INCREASED	Investigations	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0011 events1 affected51 at risk EG0020 events0 affected52 at risk
ASPARTATE AMINOTRANSFERASE INCREASED	Investigations	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0011 events1 affected51 at risk EG0020 events0 affected52 at risk
WEIGHT INCREASED	Investigations	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0012 events2 affected51 at risk EG0020 events0 affected52 at risk
DECREASED APPETITE	Metabolism and nutrition disorders	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0010 events0 affected51 at risk EG0021 events1 affected52 at risk
ARTHRALGIA	Musculoskeletal and connective tissue disorders	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0012 events2 affected51 at risk EG0023 events2 affected52 at risk
BALANCE DISORDER	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0011 events1 affected51 at risk EG0024 events4 affected52 at risk
DIZZINESS	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0004 events4 affected51 at risk EG0014 events3 affected51 at risk EG00210 events10 affected52 at risk
DYSARTHRIA	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0010 events0 affected51 at risk EG0022 events2 affected52 at risk
HEADACHE	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0003 events3 affected51 at risk EG0018 events4 affected51 at risk EG00212 events6 affected52 at risk
MEMORY IMPAIRMENT	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0012 events2 affected51 at risk EG0021 events1 affected52 at risk
SOMNOLENCE	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0004 events4 affected51 at risk EG0017 events6 affected51 at risk EG0027 events7 affected52 at risk
TREMOR	Nervous system disorders	MedDRA 27.0	Systematic Assessment	EG0001 events1 affected51 at risk EG0010 events0 affected51 at risk EG0022 events2 affected52 at risk
ANXIETY	Psychiatric disorders	MedDRA 27.0	Systematic Assessment	EG0000 events0 affected51 at risk EG0010 events0 affected51 at risk EG0024 events3 affected52 at risk
APATHY	Psychiatric disorders	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0010 events0 affected51 at risk EG0022 events2 affected52 at risk
INSOMNIA	Psychiatric disorders	MedDRA 27.0	Systematic Assessment	EG0005 events5 affected51 at risk EG0011 events1 affected51 at risk EG0022 events2 affected52 at risk
IRRITABILITY	Psychiatric disorders	MedDRA 27.0	Systematic Assessment	EG0001 events1 affected51 at risk EG0012 events2 affected51 at risk EG0023 events3 affected52 at risk
RHINORRHOEA	Respiratory, thoracic and mediastinal disorders	MedDRA 27.0	Systematic Assessment	EG0002 events2 affected51 at risk EG0010 events0 affected51 at risk EG0021 events1 affected52 at risk

ID	Term
D012640	Seizures
D004828	Epilepsies, Partial

Ancestor Terms

ID	Term
D009461	Neurologic Manifestations
D009422	Nervous System Diseases
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms
D004827	Epilepsy
D001927	Brain Diseases
D002493	Central Nervous System Diseases

ID	Term
C000630159	PF-06372865

ParticipantsBG003154

ParticipantsBG003153

CVL-865 tablets were administered orally as 5 mg twice a day (BID) for 1 week followed by 12.5 mg for another week during the Titration Phase, and then 25 mg BID during the 8-week Maintenance Phase. For participants not enrolling into the open-label extension trial, following the Maintenance Phase the dose was gradually decreased over a 3-week Taper Phase.

Units	Counts
Participants	OG00044 OG00148

Title	Measurements
	OG0005.66± 8.858 OG0014.98± 5.982 OG0022.74± 4.506 OG0033.84± 5.370

Title	Measurements
	OG0006.81± 10.391 OG0016.53± 9.010 OG0023.26± 5.018 OG0034.88± 7.414

Title	Measurements
	OG0006.20± 8.888 OG0016.44± 9.974 OG0023.29± 5.130 OG0034.87± 8.044

Title	Measurements
	OG0005.76± 9.269 OG0016.27± 8.688 OG0023.21± 6.111 OG0034.75± 7.639

Title	Measurements
	OG0005.44± 9.939 OG0016.21± 8.313 OG0023.29± 6.070 OG0034.79± 7.408

Title	Measurements
	OG0005.96± 9.864 OG0016.40± 8.520 OG0024.65± 8.235 OG0035.56± 8.381

Title	Measurements
	OG0006.62± 10.797 OG0015.23± 6.883 OG0023.60± 7.063 OG0034.45± 6.975

Title	Measurements
	OG0003.5± 1.11 OG0013.2± 1.06 OG0023.0± 1.41 OG0033.1± 1.24

Title	Measurements
	OG0003.3± 1.00 OG0013.0± 1.02 OG0023.0± 1.36 OG0033.0± 1.19

Title	Measurements
	OG000-0.2± 0.97 OG001-0.2± 1.05 OG002-0.6± 0.91 OG003-0.4± 1.00

Title	Measurements
	OG000-0.3± 0.97 OG001-0.3± 1.09 OG002-0.7± 1.09 OG003-0.5± 1.10

Title	Measurements
	OG0003.5± 0.84 OG0013.3± 1.02 OG0022.9± 1.23 OG0033.1± 1.15

Title	Measurements
	OG0003.3± 0.96 OG0013.3± 0.98 OG0022.8± 1.46 OG0033.0± 1.25