Trial Outcomes & Findings for A Trial of the Efficacy and Safety of CVL-865 as Adjunctive Therapy in the Treatment of Focal Onset Seizures (NCT NCT04244175)

Last Updated: 2025-05-30

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

154 participants

Primary outcome timeframe

Baseline Period; Maintenance Phase Days 15 through 71

Results posted on

2025-05-30

Participant Flow

This trial was conducted at 62 sites in 7 countries.

Participants were randomized in a 1:1:1 ratio to one of three treatment groups: Placebo, CVL-865 7.5 mg twice a day (BID), and CVL-865 25 mg BID.

Participant milestones

Participant milestones
Measure	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.	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.	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.
Overall Study STARTED	51	51	52
Overall Study COMPLETED	44	44	42
Overall Study NOT COMPLETED	7	7	10

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.
Overall Study Adverse Event	3	2	5
Overall Study Lack of Efficacy	1	0	1
Overall Study Lost to Follow-up	1	0	0
Overall Study Non-compliance with study drug	1	0	1
Overall Study Protocol deviation	0	1	0
Overall Study Withdrawal by Subject	1	3	1
Overall Study Other, not specified	0	1	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=51 Participants 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.	CVL-865 7.5 mg BID n=51 Participants 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.	CVL-865 25 mg BID n=52 Participants 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.	Total n=154 Participants Total of all reporting groups
Age, Continuous	40.3 years STANDARD_DEVIATION 13.38 • n=51 Participants	41.4 years STANDARD_DEVIATION 11.04 • n=51 Participants	43.1 years STANDARD_DEVIATION 12.88 • n=52 Participants	41.6 years STANDARD_DEVIATION 12.45 • n=154 Participants
Sex: Female, Male Female	29 Participants n=51 Participants	28 Participants n=51 Participants	23 Participants n=52 Participants	80 Participants n=154 Participants
Sex: Female, Male Male	22 Participants n=51 Participants	23 Participants n=51 Participants	29 Participants n=52 Participants	74 Participants n=154 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=51 Participants	7 Participants n=51 Participants	9 Participants n=52 Participants	21 Participants n=154 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	46 Participants n=51 Participants	43 Participants n=51 Participants	42 Participants n=52 Participants	131 Participants n=154 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=51 Participants	1 Participants n=51 Participants	1 Participants n=52 Participants	2 Participants n=154 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=51 Participants	0 Participants n=51 Participants	1 Participants n=52 Participants	1 Participants n=154 Participants
Race/Ethnicity, Customized Asian	2 Participants n=51 Participants	0 Participants n=51 Participants	3 Participants n=52 Participants	5 Participants n=154 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=51 Participants	2 Participants n=51 Participants	2 Participants n=52 Participants	4 Participants n=154 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	2 Participants n=51 Participants	1 Participants n=51 Participants	2 Participants n=52 Participants	5 Participants n=154 Participants
Race/Ethnicity, Customized White	46 Participants n=51 Participants	46 Participants n=51 Participants	42 Participants n=52 Participants	134 Participants n=154 Participants
Race/Ethnicity, Customized Other	1 Participants n=51 Participants	2 Participants n=51 Participants	1 Participants n=52 Participants	4 Participants n=154 Participants
Race/Ethnicity, Customized Multiple	0 Participants n=51 Participants	0 Participants n=51 Participants	1 Participants n=52 Participants	1 Participants n=154 Participants
Duration of Epilepsy	25.88 years STANDARD_DEVIATION 14.595 • n=51 Participants • Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)	22.98 years STANDARD_DEVIATION 14.896 • n=50 Participants • Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)	23.54 years STANDARD_DEVIATION 13.335 • n=52 Participants • Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)	24.14 years STANDARD_DEVIATION 14.243 • n=153 Participants • Full analysis set: All randomized participants who receive at least 1 dose of investigational medicinal product (IMP)

PRIMARY outcome

Timeframe: Baseline Period; Maintenance Phase Days 15 through 71

Population: 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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=46 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=93 Participants 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.	Placebo n=50 Participants 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.	CVL-865 25 mg BID n=47 Participants 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.
Response Ratio (RRatio)	-22.45 RRatio Standard Deviation 26.393	-24.19 RRatio Standard Deviation 30.041	-24.06 RRatio Standard Deviation 33.441	-25.90 RRatio Standard Deviation 33.428

SECONDARY outcome

Timeframe: Baseline Period; Maintenance Phase Days 15 through 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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=46 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=93 Participants 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.	Placebo n=50 Participants 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.	CVL-865 25 mg BID n=47 Participants 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.
Percentage Change From Baseline in Focal Onset Seizure Frequency Per Week Over the Maintenance Phase	-27.2 Percentage change from Baseline	-28.5 Percentage change from Baseline	-26.2 Percentage change from Baseline	-29.8 Percentage change from Baseline

SECONDARY outcome

Timeframe: Baseline Period; Maintenance Phase Days 15 through 71

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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=46 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=93 Participants 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.	Placebo n=50 Participants 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.	CVL-865 25 mg BID n=47 Participants 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.
Percentage of Participants With 50 Percent (%) Responder Rate	34.8 percentage of participants	36.6 percentage of participants	30.0 percentage of participants	38.3 percentage of participants

SECONDARY outcome

Timeframe: Maintenance Phase Days 15 through 71

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

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=46 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=93 Participants 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.	Placebo n=50 Participants 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.	CVL-865 25 mg BID n=47 Participants 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.
Percentage of Seizure-free Participants During the Maintenance Phase	2.2 percentage of participants	3.2 percentage of participants	6.0 percentage of participants	4.3 percentage of participants

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=46 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=93 Participants 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.	Placebo n=50 Participants 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.	CVL-865 25 mg BID n=47 Participants 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.
Weekly Seizure Rate During the Maintenance Phase Maintenance Phase Week 1	5.20 Seizures/week Standard Deviation 5.867	3.95 Seizures/week Standard Deviation 5.472	6.41 Seizures/week Standard Deviation 10.772	2.71 Seizures/week Standard Deviation 4.804
Weekly Seizure Rate During the Maintenance Phase Maintenance Phase Week 2	4.98 Seizures/week Standard Deviation 5.982	3.84 Seizures/week Standard Deviation 5.370	5.66 Seizures/week Standard Deviation 8.858	2.74 Seizures/week Standard Deviation 4.506
Weekly Seizure Rate During the Maintenance Phase Maintenance Phase Week 3	6.53 Seizures/week Standard Deviation 9.010	4.88 Seizures/week Standard Deviation 7.414	6.81 Seizures/week Standard Deviation 10.391	3.26 Seizures/week Standard Deviation 5.018
Weekly Seizure Rate During the Maintenance Phase Maintenance Phase Week 4	6.44 Seizures/week Standard Deviation 9.974	4.87 Seizures/week Standard Deviation 8.044	6.20 Seizures/week Standard Deviation 8.888	3.29 Seizures/week Standard Deviation 5.130
Weekly Seizure Rate During the Maintenance Phase Maintenance Phase Week 5	6.27 Seizures/week Standard Deviation 8.688	4.75 Seizures/week Standard Deviation 7.639	5.76 Seizures/week Standard Deviation 9.269	3.21 Seizures/week Standard Deviation 6.111
Weekly Seizure Rate During the Maintenance Phase Maintenance Phase Week 6	6.21 Seizures/week Standard Deviation 8.313	4.79 Seizures/week Standard Deviation 7.408	5.44 Seizures/week Standard Deviation 9.939	3.29 Seizures/week Standard Deviation 6.070
Weekly Seizure Rate During the Maintenance Phase Maintenance Phase Week 7	6.40 Seizures/week Standard Deviation 8.520	5.56 Seizures/week Standard Deviation 8.381	5.96 Seizures/week Standard Deviation 9.864	4.65 Seizures/week Standard Deviation 8.235
Weekly Seizure Rate During the Maintenance Phase Maintenance Phase Week 8	5.23 Seizures/week Standard Deviation 6.883	4.45 Seizures/week Standard Deviation 6.975	6.62 Seizures/week Standard Deviation 10.797	3.60 Seizures/week Standard Deviation 7.063

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=46 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=93 Participants 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.	Placebo n=50 Participants 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.	CVL-865 25 mg BID n=47 Participants 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.
Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 15	3.3 units on a scale Standard Deviation 0.96	3.1 units on a scale Standard Deviation 1.13	3.5 units on a scale Standard Deviation 0.76	3.0 units on a scale Standard Deviation 1.27
Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 43	3.2 units on a scale Standard Deviation 1.06	3.1 units on a scale Standard Deviation 1.24	3.5 units on a scale Standard Deviation 1.11	3.0 units on a scale Standard Deviation 1.41
Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 71	3.0 units on a scale Standard Deviation 1.02	3.0 units on a scale Standard Deviation 1.19	3.3 units on a scale Standard Deviation 1.00	3.0 units on a scale Standard Deviation 1.36

SECONDARY outcome

Timeframe: Baseline, 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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=46 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=91 Participants 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.	Placebo n=50 Participants 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.	CVL-865 25 mg BID n=45 Participants 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.
Change From Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 15	0.0 units on a scale Standard Deviation 0.94	-0.2 units on a scale Standard Deviation 0.92	-0.2 units on a scale Standard Deviation 0.66	-0.3 units on a scale Standard Deviation 0.87
Change From Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 43	-0.2 units on a scale Standard Deviation 1.05	-0.4 units on a scale Standard Deviation 1.00	-0.2 units on a scale Standard Deviation 0.97	-0.6 units on a scale Standard Deviation 0.91
Change From Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 71	-0.3 units on a scale Standard Deviation 1.09	-0.5 units on a scale Standard Deviation 1.10	-0.3 units on a scale Standard Deviation 0.97	-0.7 units on a scale Standard Deviation 1.09

SECONDARY outcome

Timeframe: Baseline, 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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=46 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=93 Participants 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.	Placebo n=50 Participants 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.	CVL-865 25 mg BID n=47 Participants 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.
Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 15	3.4 units on a scale Standard Deviation 0.83	3.2 units on a scale Standard Deviation 0.88	3.5 units on a scale Standard Deviation 0.71	3.1 units on a scale Standard Deviation 0.91
Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 43	3.3 units on a scale Standard Deviation 1.02	3.1 units on a scale Standard Deviation 1.15	3.5 units on a scale Standard Deviation 0.84	2.9 units on a scale Standard Deviation 1.23
Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 Maintenance Phase Day 71	3.3 units on a scale Standard Deviation 0.98	3.0 units on a scale Standard Deviation 1.25	3.3 units on a scale Standard Deviation 0.96	2.8 units on a scale Standard Deviation 1.46

SECONDARY outcome

Timeframe: Baseline, 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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=44 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=90 Participants 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.	Placebo n=46 Participants 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.	CVL-865 25 mg BID n=46 Participants 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.
Change From Baseline in Quality of Life in Epilepsy-31 (QOLIE-31) Overall Score at Maintenance Phase Day 71	2.08 units on a scale Standard Deviation 12.717	2.91 units on a scale Standard Deviation 12.445	0.29 units on a scale Standard Deviation 9.859	3.70 units on a scale Standard Deviation 12.267

SECONDARY outcome

Timeframe: Baseline, Maintenance Phase Day 71

Population: 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.

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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=44 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=90 Participants 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.	Placebo n=48 Participants 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.	CVL-865 25 mg BID n=46 Participants 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.
Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 HUI-3	0.110 units on a scale Standard Deviation 0.3448	0.048 units on a scale Standard Deviation 0.4027	-0.025 units on a scale Standard Deviation 0.3961	-0.012 units on a scale Standard Deviation 0.4469
Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 HUI-2	0.052 units on a scale Standard Deviation 0.2162	0.018 units on a scale Standard Deviation 0.2679	-0.029 units on a scale Standard Deviation 0.2579	-0.014 units on a scale Standard Deviation 0.3084

SECONDARY outcome

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

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

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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=50 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=102 Participants 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.	Placebo n=51 Participants 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.	CVL-865 25 mg BID n=52 Participants 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.
Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) Any TEAE	33 Participants	79 Participants	28 Participants	46 Participants
Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) TESAE	4 Participants	5 Participants	1 Participants	1 Participants

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=50 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=102 Participants 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.	Placebo n=51 Participants 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.	CVL-865 25 mg BID n=52 Participants 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.
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) Change from Baseline in QTcF Interval, > 60 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) Absolute QTcF Interval (msec), > 450 and ≤480 msec	1 Participants	3 Participants	0 Participants	2 Participants
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) Absolute QTcF Interval (msec), > 480 and ≤500 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) Absolute QTcF Interval (msec), > 500 msec	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) Change from Baseline in QTcF Interval, > 30 - 60 msec	2 Participants	3 Participants	4 Participants	1 Participants

SECONDARY outcome

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

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

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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=50 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=102 Participants 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.	Placebo n=51 Participants 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.	CVL-865 25 mg BID n=52 Participants 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.
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Systolic Blood Pressure < 90 mmHg	1 Participants	1 Participants	0 Participants	0 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Systolic Blood Pressure > 140 mmHg	0 Participants	1 Participants	4 Participants	1 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Diastolic Blood Pressure < 50 mmHg	1 Participants	1 Participants	0 Participants	0 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Diastolic Blood Pressure > 90 mmHg	0 Participants	2 Participants	4 Participants	2 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Heart Rate < 60 beats/min	6 Participants	20 Participants	6 Participants	14 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Heart Rate > 100 beats/min	1 Participants	1 Participants	2 Participants	0 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Respiratory Rate < 12 breaths/min	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Respiratory Rate > 20 breaths/min	0 Participants	1 Participants	0 Participants	1 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Temperature < 36 °C	2 Participants	9 Participants	2 Participants	7 Participants
Number of Participants With Clinically Significant Changes in Vital Sign Measurements Temperature > 38 °C	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=50 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=102 Participants 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.	Placebo n=51 Participants 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.	CVL-865 25 mg BID n=52 Participants 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.
Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results Clinically Significant Changes in Physical Examination	1 Participants	3 Participants	3 Participants	2 Participants
Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results Clinically Significant Changes in Neurological Examination	1 Participants	6 Participants	5 Participants	5 Participants

SECONDARY outcome

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

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

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).

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=50 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=102 Participants 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.	Placebo n=51 Participants 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.	CVL-865 25 mg BID n=52 Participants 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.
Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) Suicidal Ideation: (1) Wish to be dead	0 Participants	2 Participants	0 Participants	2 Participants
Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) Suicidal Ideation: (2) Non-specific active suicidal thoughts	0 Participants	1 Participants	0 Participants	1 Participants
Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) Suicidal Ideation: (3) Active suicidal ideation with any methods (not plan) without intent to act	1 Participants	1 Participants	0 Participants	0 Participants
Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) Suicidal Ideation: (4) Active suicidal ideation with some intent to act, without specific plan	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) Suicidal Ideation: (5) Active suicidal ideation with specific plan and intent	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

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

Population: 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.

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.

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=10 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=20 Participants 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.	Placebo n=7 Participants 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.	CVL-865 25 mg BID n=10 Participants 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.
Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment Taper Phase Day 78	0.7 units on a scale Standard Deviation 3.09	-0.1 units on a scale Standard Deviation 2.66	-0.9 units on a scale Standard Deviation 3.13	-1.0 units on a scale Standard Deviation 1.87
Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment Taper Phase Day 85	-0.4 units on a scale Standard Deviation 5.64	-0.3 units on a scale Standard Deviation 4.64	-1.7 units on a scale Standard Deviation 3.35	-0.2 units on a scale Standard Deviation 3.56
Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment Taper Phase Day 92	-0.5 units on a scale Standard Deviation 4.20	0.3 units on a scale Standard Deviation 3.93	-1.1 units on a scale Standard Deviation 4.85	1.1 units on a scale Standard Deviation 3.66
Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment Safety Follow-up Day 99	-0.8 units on a scale Standard Deviation 6.65	0.7 units on a scale Standard Deviation 6.29	-1.7 units on a scale Standard Deviation 5.31	2.3 units on a scale Standard Deviation 5.79
Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment Safety Follow-up Day 120	-0.2 units on a scale Standard Deviation 6.09	0.4 units on a scale Standard Deviation 5.16	-1.0 units on a scale Standard Deviation 5.10	0.9 units on a scale Standard Deviation 4.31

SECONDARY outcome

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

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

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

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=50 Participants 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.	CVL-865 7.5 mg BID / 25 mg BID n=102 Participants 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.	Placebo n=51 Participants 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.	CVL-865 25 mg BID n=52 Participants 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.
Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) Abuse-related AEs	10 Participants	30 Participants	9 Participants	20 Participants
Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) AEs related to Medication Handling Irregularities	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

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

Population: 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.

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

Outcome measures

Outcome measures
Measure	CVL-865 7.5 mg BID n=48 Participants 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.	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.	Placebo n=44 Participants 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.	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.
Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 Maintenance Phase Day 71	167.96 ng/mL Standard Deviation 160.999	—	32.45 ng/mL Standard Deviation 29.433	—
Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 Maintenance Phase Day 15	69.64 ng/mL Standard Deviation 56.166	—	30.99 ng/mL Standard Deviation 29.086	—
Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 Maintenance Phase Day 43	151.63 ng/mL Standard Deviation 125.931	—	34.60 ng/mL Standard Deviation 33.554	—
Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 Taper Phase Day 92	29.02 ng/mL Standard Deviation 34.133	—	9.74 ng/mL Standard Deviation 14.978	—

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 24 other events

Deaths: 0 deaths

CVL-865 7.5 mg BID

Serious events: 4 serious events

Other events: 26 other events

Deaths: 0 deaths

CVL-865 25 mg BID

Serious events: 2 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=51 participants at risk 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.	CVL-865 7.5 mg BID n=51 participants at risk 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.	CVL-865 25 mg BID n=52 participants at risk 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.
Blood and lymphatic system disorders THROMBOCYTOPENIA	2.0% 1/51 • Number of events 1 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	0.00% 0/52 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.
Hepatobiliary disorders CHOLECYSTITIS	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	1.9% 1/52 • Number of events 1 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.
Injury, poisoning and procedural complications SKIN LACERATION	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	2.0% 1/51 • Number of events 1 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	0.00% 0/52 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.
Nervous system disorders GENERALISED TONIC-CLONIC SEIZURE	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	1.9% 1/52 • Number of events 1 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.
Nervous system disorders MYOCLONUS	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	2.0% 1/51 • Number of events 1 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	0.00% 0/52 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.
Psychiatric disorders SUICIDAL IDEATION	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	2.0% 1/51 • Number of events 1 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	0.00% 0/52 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.
Vascular disorders PERIPHERAL ARTERY OCCLUSION	0.00% 0/51 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	2.0% 1/51 • Number of events 1 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.	0.00% 0/52 • All-cause mortality and adverse event tables include events reported from the time informed consent was signed to the end of the study. The median time on follow-up was 127 days for the Placebo group,129 days for the CVL-865 7.5 mg BID group, and 127 days for the CVL-865 25 mg BID group.

Other adverse events

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