Seizures
Conditions
Keywords
CVL-865, Anti-epileptic drugs (AEDs), Focal epilepsy, γ-aminobutyric acid (GABA), Partial seizure, PF-06372865, Darigabat
Brief summary
The goal of this clinical trial is to learn if CVL-865, when taken regularly with other anti-seizure medicines, works to prevent seizures in adults with drug-resistant focal onset seizures. It will also learn about the safety of CVL-865. The main question it aims to answer is whether CVL-865, when taken regularly with other anti-seizure medicines, lowers the number of seizures in those with a diagnosis of epilepsy with drug-resistant focal onset seizures. This study has an 8-week Screening/Baseline Period, a 13-week Treatment Period (including a 2-week Titration Phase, an 8-week Maintenance Phase, and a 3-week Taper Phase), and a 4-week Safety Follow-Up Period. Participants will take CVL-865 or a placebo twice a day during the 10-13 week Treatment Period, visit the clinic every few weeks for checkups, tests, and surveys, and fill out an e-Diary.
Interventions
DRUGPlacebo
Participants received CVL-865 matched placebo tablets orally twice a day (BID) during the Treatment Period.
DRUGCVL-865
Participants received CVL-865 tablets orally twice a day (BID) up to the maximum dose of 7.5 mg BID or 25 mg BID during the Treatment Period.
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Ratio (RRatio) | Baseline Period; Maintenance Phase Days 15 through 71 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 50 Percent (%) Responder Rate | 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. |
| Percentage of Seizure-free Participants During the Maintenance Phase | Maintenance Phase Days 15 through 71 | Seizure freedom is defined as no seizures during the Maintenance Phase. |
| Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Weeks 1, 2, 3, 4, 5, 6, 7, 8 | Seizure frequency is defined as the total number of focal onset seizures over the treatment period of interest divided by the total number of days with no missing seizure counts in the corresponding period multiplied by 7. |
| Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 | 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. |
| Change From Baseline in Clinical Global Impression-Severity of Symptoms Scale (CGI-S) Score at Maintenance Phase Days 15, 43, and 71 | 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. |
| Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | 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. |
| Change From Baseline in Quality of Life in Epilepsy-31 (QOLIE-31) Overall Score at Maintenance Phase Day 71 | 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. |
| Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 | Baseline, 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. |
| Percentage Change From Baseline in Focal Onset Seizure Frequency Per Week Over the Maintenance Phase | 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. |
| Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Baseline; From first dose of study drug until 30 days following last dose of study drug (up to Day 120) | 12-lead electrocardiogram (ECG) recordings were obtained after the participant had been supine and at rest for at least 5 minutes. |
| Number of Participants With Clinically Significant Changes in Vital Sign Measurements | From first dose of study drug until 30 days following last dose of study drug (up to Day 120) | 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. |
| Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Baseline; From first dose of study drug until 30 days following last dose of study drug (up to Day 120) | The number of participants with clinically significant changes in physical and neurological examination results was documented. |
| Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | From first dose of study drug until 30 days following last dose of study drug (up to Day 120) | 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). |
| Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Maintenance Phase Day 71, Taper Phase Days 78, 85, and 92, and Safety Follow-up Days 99 and 120 | The modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) is a sensitive instrument to measure withdrawal under conditions where there is a taper of medication (rather than abrupt discontinuation). It consists of 17-items that monitor the type and severity of BZD withdrawal symptoms such as irritability, fatigue, appetite, and sleeplessness. The total score ranges from 1 to 68 with higher scores indicating more severe withdrawal. Baseline is defined as the last on-treatment assessment on Day 71. Negative changes from Baseline indicate a reduction in withdrawal symptoms. |
| Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | From first dose of study drug until 30 days following last dose of study drug (up to Day 120) | Adverse events potentially related to abuse or dependence of the investigational medicinal product (IMP) were documented. |
| Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 | 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. |
| Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | From first dose of study drug until 30 days following last dose of study drug (up to Day 120) | 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. |
Countries
Australia, Poland, Serbia, South Korea, Spain, Ukraine, United States
Participant flow
Recruitment details
This trial was conducted at 62 sites in 7 countries.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 |
| 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 |
| 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 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 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 | Other, not specified | 0 | 1 | 2 |
| Overall Study | Protocol deviation | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | CVL-865 7.5 mg BID | CVL-865 25 mg BID | Total |
|---|---|---|---|---|
| Age, Continuous | 40.3 years STANDARD_DEVIATION 13.38 | 41.4 years STANDARD_DEVIATION 11.04 | 43.1 years STANDARD_DEVIATION 12.88 | 41.6 years STANDARD_DEVIATION 12.45 |
| Duration of Epilepsy | 25.88 years STANDARD_DEVIATION 14.595 | 22.98 years STANDARD_DEVIATION 14.896 | 23.54 years STANDARD_DEVIATION 13.335 | 24.14 years STANDARD_DEVIATION 14.243 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 7 Participants | 9 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 43 Participants | 42 Participants | 131 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 46 Participants | 46 Participants | 42 Participants | 134 Participants |
| Sex: Female, Male Female | 29 Participants | 28 Participants | 23 Participants | 80 Participants |
| Sex: Female, Male Male | 22 Participants | 23 Participants | 29 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 51 | 0 / 52 |
| other Total, other adverse events | 24 / 51 | 26 / 51 | 38 / 52 |
| serious Total, serious adverse events | 1 / 51 | 4 / 51 | 2 / 52 |
Outcome results
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Response Ratio (RRatio) | -24.06 RRatio | Standard Deviation 33.441 |
| CVL-865 7.5 mg BID | Response Ratio (RRatio) | -22.45 RRatio | Standard Deviation 26.393 |
| CVL-865 25 mg BID | Response Ratio (RRatio) | -25.90 RRatio | Standard Deviation 33.428 |
| CVL-865 7.5 mg BID / 25 mg BID | Response Ratio (RRatio) | -24.19 RRatio | Standard Deviation 30.041 |
Comparison: CVL-865 25 mg BID vs Placebop-value: =0.98690% CI: [-10.38, 10.61]ANCOVA
Comparison: CVL-865 7.5 mg BID vs Placebop-value: =0.82390% CI: [-9.04, 11.87]ANCOVA
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebop-value: =0.88890% CI: [-8.23, 9.76]ANCOVA
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.
Time frame: Baseline, Maintenance Phase Days 15, 43, and 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 | -0.2 units on a scale | Standard Deviation 0.66 |
| Placebo | 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 0.97 |
| Placebo | 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 0.97 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 25 mg BID | 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 | -0.6 units on a scale | Standard Deviation 0.91 |
| CVL-865 25 mg BID | 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 | -0.3 units on a scale | Standard Deviation 0.87 |
| CVL-865 25 mg BID | 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 | -0.7 units on a scale | Standard Deviation 1.09 |
| CVL-865 7.5 mg BID / 25 mg BID | 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 | -0.2 units on a scale | Standard Deviation 0.92 |
| CVL-865 7.5 mg BID / 25 mg BID | 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 | -0.5 units on a scale | Standard Deviation 1.1 |
| CVL-865 7.5 mg BID / 25 mg BID | 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 | -0.4 units on a scale | Standard Deviation 1 |
Comparison: CVL-865 25 mg BID vs Placebo (Day 15)p-value: =0.76790% CI: [-0.3, 0.2]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 15)p-value: =0.17890% CI: [0, 0.5]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 15)p-value: =0.54290% CI: [-0.1, 0.3]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 25 mg BID vs Placebo (Day 43)p-value: =0.10690% CI: [-0.6, 0]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 43)p-value: =0.66390% CI: [-0.2, 0.4]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 43)p-value: =0.48890% CI: [-0.4, 0.2]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 25 mg BID vs Placebo (Day 71)p-value: =0.190% CI: [-0.7, 0]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 71)p-value: =0.96990% CI: [-0.3, 0.3]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 71)p-value: =0.34490% CI: [-0.4, 0.1]Mixed Model for Repeated Measures (MMRM)
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 | HUI-2 | -0.029 units on a scale | Standard Deviation 0.2579 |
| Placebo | Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 | HUI-3 | -0.025 units on a scale | Standard Deviation 0.3961 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 25 mg BID | Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 | HUI-2 | -0.014 units on a scale | Standard Deviation 0.3084 |
| CVL-865 25 mg BID | Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 | HUI-3 | -0.012 units on a scale | Standard Deviation 0.4469 |
| CVL-865 7.5 mg BID / 25 mg BID | Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 | HUI-2 | 0.018 units on a scale | Standard Deviation 0.2679 |
| CVL-865 7.5 mg BID / 25 mg BID | Change From Baseline in Health Utilities Index (HUI) Utility Score at Maintenance Phase Day 71 | HUI-3 | 0.048 units on a scale | Standard Deviation 0.4027 |
Comparison: CVL-865 25 mg BID vs Placebo (HUI-2)p-value: =0.78890% CI: [-0.096, 0.069]ANCOVA
Comparison: CVL-865 7.5 mg BID vs Placebo (HUI-2)p-value: =0.12690% CI: [-0.006, 0.16]ANCOVA
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (HUI-2)p-value: =0.46190% CI: [-0.039, 0.103]ANCOVA
Comparison: CVL-865 25 mg BID vs Placebo (HUI-3)p-value: =0.66190% CI: [-0.154, 0.089]ANCOVA
Comparison: CVL-865 7.5 mg BID vs Placebo (HUI-3)p-value: =0.12490% CI: [-0.008, 0.237]ANCOVA
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (HUI-3)p-value: =0.51890% CI: [-0.064, 0.146]ANCOVA
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Quality of Life in Epilepsy-31 (QOLIE-31) Overall Score at Maintenance Phase Day 71 | 0.29 units on a scale | Standard Deviation 9.859 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 25 mg BID | Change From Baseline in Quality of Life in Epilepsy-31 (QOLIE-31) Overall Score at Maintenance Phase Day 71 | 3.70 units on a scale | Standard Deviation 12.267 |
| CVL-865 7.5 mg BID / 25 mg BID | Change From Baseline in Quality of Life in Epilepsy-31 (QOLIE-31) Overall Score at Maintenance Phase Day 71 | 2.91 units on a scale | Standard Deviation 12.445 |
Comparison: CVL-865 25 mg BID vs Placebop-value: =0.82990% CI: [-4.23, 3.26]ANCOVA
Comparison: CVL-865 7.5 mg BID vs Placebop-value: =0.92790% CI: [-3.87, 3.46]ANCOVA
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebop-value: =0.85990% CI: [-3.57, 2.88]ANCOVA
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 78 | -0.9 units on a scale | Standard Deviation 3.13 |
| Placebo | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Safety Follow-up Day 120 | -1.0 units on a scale | Standard Deviation 5.1 |
| Placebo | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Safety Follow-up Day 99 | -1.7 units on a scale | Standard Deviation 5.31 |
| Placebo | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 92 | -1.1 units on a scale | Standard Deviation 4.85 |
| Placebo | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 85 | -1.7 units on a scale | Standard Deviation 3.35 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 4.2 |
| CVL-865 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 85 | -0.2 units on a scale | Standard Deviation 3.56 |
| CVL-865 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 78 | -1.0 units on a scale | Standard Deviation 1.87 |
| CVL-865 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 92 | 1.1 units on a scale | Standard Deviation 3.66 |
| CVL-865 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Safety Follow-up Day 120 | 0.9 units on a scale | Standard Deviation 4.31 |
| CVL-865 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Safety Follow-up Day 99 | 2.3 units on a scale | Standard Deviation 5.79 |
| CVL-865 7.5 mg BID / 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Safety Follow-up Day 120 | 0.4 units on a scale | Standard Deviation 5.16 |
| CVL-865 7.5 mg BID / 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 78 | -0.1 units on a scale | Standard Deviation 2.66 |
| CVL-865 7.5 mg BID / 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 85 | -0.3 units on a scale | Standard Deviation 4.64 |
| CVL-865 7.5 mg BID / 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Taper Phase Day 92 | 0.3 units on a scale | Standard Deviation 3.93 |
| CVL-865 7.5 mg BID / 25 mg BID | Change in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) From Last On-treatment Assessment | Safety Follow-up Day 99 | 0.7 units on a scale | Standard Deviation 6.29 |
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.
Time frame: Baseline, Maintenance Phase Days 15, 43, and 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 15 | 3.5 units on a scale | Standard Deviation 0.71 |
| Placebo | 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 0.96 |
| Placebo | Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 43 | 3.5 units on a scale | Standard Deviation 0.84 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 25 mg BID | Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 43 | 2.9 units on a scale | Standard Deviation 1.23 |
| CVL-865 25 mg BID | Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 15 | 3.1 units on a scale | Standard Deviation 0.91 |
| CVL-865 25 mg BID | Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 71 | 2.8 units on a scale | Standard Deviation 1.46 |
| CVL-865 7.5 mg BID / 25 mg BID | Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 15 | 3.2 units on a scale | Standard Deviation 0.88 |
| CVL-865 7.5 mg BID / 25 mg BID | Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 71 | 3.0 units on a scale | Standard Deviation 1.25 |
| CVL-865 7.5 mg BID / 25 mg BID | Clinical Global Impression-Improvement Scale (CGI-I) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 43 | 3.1 units on a scale | Standard Deviation 1.15 |
Comparison: CVL-865 25 mg BID vs Placebo (Day 15)p-value: =0.0190% CI: [-0.7, -0.2]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 15)p-value: =0.37690% CI: [-0.4, 0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 15)p-value: =0.04490% CI: [-0.5, -0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 25 mg BID vs Placebo (Day 43)p-value: =0.00590% CI: [-1, -0.3]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 43)p-value: =0.54990% CI: [-0.5, 0.2]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 43)p-value: =0.04890% CI: [-0.7, -0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 25 mg BID vs Placebo (Day 71)p-value: =0.00590% CI: [-1, -0.3]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 71)p-value: =0.54990% CI: [-0.5, 0.2]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 71)p-value: =0.04890% CI: [-0.7, -0.1]Mixed Model for Repeated Measures (MMRM)
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.
Time frame: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | AEs related to Medication Handling Irregularities | 0 Participants |
| Placebo | Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | Abuse-related AEs | 9 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | AEs related to Medication Handling Irregularities | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | Abuse-related AEs | 10 Participants |
| CVL-865 25 mg BID | Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | AEs related to Medication Handling Irregularities | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | Abuse-related AEs | 20 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | AEs related to Medication Handling Irregularities | 0 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Adverse Events That Are Abuse-related or Involve Medication Handling Irregularities (MHI) | Abuse-related AEs | 30 Participants |
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.
Time frame: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 480 and ≤500 msec | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Change from Baseline in QTcF Interval, > 30 - 60 msec | 4 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 500 msec | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Change from Baseline in QTcF Interval, > 60 msec | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 450 and ≤480 msec | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 450 and ≤480 msec | 1 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 480 and ≤500 msec | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Change from Baseline in QTcF Interval, > 60 msec | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Change from Baseline in QTcF Interval, > 30 - 60 msec | 2 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 500 msec | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 450 and ≤480 msec | 2 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 500 msec | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Change from Baseline in QTcF Interval, > 30 - 60 msec | 1 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 480 and ≤500 msec | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Change from Baseline in QTcF Interval, > 60 msec | 0 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 480 and ≤500 msec | 0 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Change from Baseline in QTcF Interval, > 30 - 60 msec | 3 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 500 msec | 0 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Absolute QTcF Interval (msec), > 450 and ≤480 msec | 3 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Electrocardiogram (ECGs) | Change from Baseline in QTcF Interval, > 60 msec | 0 Participants |
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.
Time frame: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Clinically Significant Changes in Physical Examination | 3 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Clinically Significant Changes in Neurological Examination | 5 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Clinically Significant Changes in Neurological Examination | 1 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Clinically Significant Changes in Physical Examination | 1 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Clinically Significant Changes in Physical Examination | 2 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Clinically Significant Changes in Neurological Examination | 5 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Clinically Significant Changes in Physical Examination | 3 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Physical and Neurological Examination Results | Clinically Significant Changes in Neurological Examination | 6 Participants |
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.
Time frame: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Systolic Blood Pressure < 90 mmHg | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Diastolic Blood Pressure < 50 mmHg | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Diastolic Blood Pressure > 90 mmHg | 4 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Heart Rate < 60 beats/min | 6 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Heart Rate > 100 beats/min | 2 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Respiratory Rate < 12 breaths/min | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Temperature < 36 °C | 2 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Temperature > 38 °C | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Systolic Blood Pressure > 140 mmHg | 4 Participants |
| Placebo | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Respiratory Rate > 20 breaths/min | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Diastolic Blood Pressure < 50 mmHg | 1 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Respiratory Rate < 12 breaths/min | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Heart Rate < 60 beats/min | 6 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Temperature < 36 °C | 2 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Diastolic Blood Pressure > 90 mmHg | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Systolic Blood Pressure < 90 mmHg | 1 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Respiratory Rate > 20 breaths/min | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Heart Rate > 100 beats/min | 1 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Systolic Blood Pressure > 140 mmHg | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Temperature > 38 °C | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Diastolic Blood Pressure < 50 mmHg | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Heart Rate < 60 beats/min | 14 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Heart Rate > 100 beats/min | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Respiratory Rate < 12 breaths/min | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Diastolic Blood Pressure > 90 mmHg | 2 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Temperature < 36 °C | 7 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Respiratory Rate > 20 breaths/min | 1 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Systolic Blood Pressure < 90 mmHg | 0 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Systolic Blood Pressure > 140 mmHg | 1 Participants |
| CVL-865 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Temperature > 38 °C | 0 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Heart Rate > 100 beats/min | 1 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Heart Rate < 60 beats/min | 20 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Diastolic Blood Pressure < 50 mmHg | 1 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Systolic Blood Pressure < 90 mmHg | 1 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Respiratory Rate > 20 breaths/min | 1 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Temperature > 38 °C | 0 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Respiratory Rate < 12 breaths/min | 0 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Systolic Blood Pressure > 140 mmHg | 1 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Temperature < 36 °C | 9 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Clinically Significant Changes in Vital Sign Measurements | Diastolic Blood Pressure > 90 mmHg | 2 Participants |
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).
Time frame: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (1) Wish to be dead | 0 Participants |
| Placebo | Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (2) Non-specific active suicidal thoughts | 0 Participants |
| Placebo | 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 | 0 Participants |
| Placebo | 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 |
| Placebo | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (1) Wish to be dead | 0 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (2) Non-specific active suicidal thoughts | 0 Participants |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 25 mg BID | Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (2) Non-specific active suicidal thoughts | 1 Participants |
| CVL-865 25 mg BID | 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 |
| CVL-865 25 mg BID | Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (1) Wish to be dead | 2 Participants |
| CVL-865 25 mg BID | 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 | 0 Participants |
| CVL-865 25 mg BID | 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 |
| CVL-865 7.5 mg BID / 25 mg BID | 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 |
| CVL-865 7.5 mg BID / 25 mg BID | 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 |
| CVL-865 7.5 mg BID / 25 mg BID | 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 |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (1) Wish to be dead | 2 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Positive Response to Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (2) Non-specific active suicidal thoughts | 1 Participants |
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.
Time frame: 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)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAE | 28 Participants |
| Placebo | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TESAE | 1 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TESAE | 4 Participants |
| CVL-865 7.5 mg BID | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAE | 33 Participants |
| CVL-865 25 mg BID | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAE | 46 Participants |
| CVL-865 25 mg BID | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TESAE | 1 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAE | 79 Participants |
| CVL-865 7.5 mg BID / 25 mg BID | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | TESAE | 5 Participants |
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.
Time frame: Maintenance Phase Days 15, 43, and 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 15 | 3.5 units on a scale | Standard Deviation 0.76 |
| Placebo | Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 71 | 3.3 units on a scale | Standard Deviation 1 |
| Placebo | Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 43 | 3.5 units on a scale | Standard Deviation 1.11 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 25 mg BID | Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 43 | 3.0 units on a scale | Standard Deviation 1.41 |
| CVL-865 25 mg BID | Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 15 | 3.0 units on a scale | Standard Deviation 1.27 |
| CVL-865 25 mg BID | 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 1.36 |
| CVL-865 7.5 mg BID / 25 mg BID | Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 15 | 3.1 units on a scale | Standard Deviation 1.13 |
| CVL-865 7.5 mg BID / 25 mg BID | 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 1.19 |
| CVL-865 7.5 mg BID / 25 mg BID | Patient's Global Impression of Change (PGI-C) Score at Maintenance Phase Days 15, 43, and 71 | Maintenance Phase Day 43 | 3.1 units on a scale | Standard Deviation 1.24 |
Comparison: CVL-865 25 mg BID vs Placebo (Day 15)p-value: =0.02190% CI: [-0.8, -0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 15)p-value: =0.34290% CI: [-0.5, 0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 15)p-value: =0.05990% CI: [-0.6, 0]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 25 mg BID vs Placebo (Day 43)p-value: =0.0490% CI: [-0.9, -0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 43)p-value: =0.15290% CI: [-0.8, 0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 43)p-value: =0.04490% CI: [-0.8, -0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 25 mg BID vs Placebo (Day 71)p-value: =0.19990% CI: [-0.7, 0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID vs Placebo (Day 71)p-value: =0.17190% CI: [-0.7, 0.1]Mixed Model for Repeated Measures (MMRM)
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo (Day 71)p-value: =0.12590% CI: [-0.7, 0]Mixed Model for Repeated Measures (MMRM)
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.
Time frame: 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. Data are presented for participants with a non-missing value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage Change From Baseline in Focal Onset Seizure Frequency Per Week Over the Maintenance Phase | -26.2 Percentage change from Baseline |
| CVL-865 7.5 mg BID | Percentage Change From Baseline in Focal Onset Seizure Frequency Per Week Over the Maintenance Phase | -27.2 Percentage change from Baseline |
| CVL-865 25 mg BID | Percentage Change From Baseline in Focal Onset Seizure Frequency Per Week Over the Maintenance Phase | -29.8 Percentage change from Baseline |
| CVL-865 7.5 mg BID / 25 mg BID | Percentage Change From Baseline in Focal Onset Seizure Frequency Per Week Over the Maintenance Phase | -28.5 Percentage change from Baseline |
Comparison: CVL-865 25 mg BID vs Placebo90% CI: [-12, 19.3]
Comparison: CVL-865 7.5 mg BID vs Placebo90% CI: [-16.1, 16.2]
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebo90% CI: [-11.4, 15.8]
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With 50 Percent (%) Responder Rate | 30.0 percentage of participants |
| CVL-865 7.5 mg BID | Percentage of Participants With 50 Percent (%) Responder Rate | 34.8 percentage of participants |
| CVL-865 25 mg BID | Percentage of Participants With 50 Percent (%) Responder Rate | 38.3 percentage of participants |
| CVL-865 7.5 mg BID / 25 mg BID | Percentage of Participants With 50 Percent (%) Responder Rate | 36.6 percentage of participants |
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebop-value: =0.51390% CI: [0.684, 2.42]Regression, Logistic
Comparison: CVL-865 25 mg BID vs Placebop-value: =0.58790% CI: [0.616, 2.618]Regression, Logistic
Comparison: CVL-865 7.5 mg BID vs Placebop-value: =0.55490% CI: [0.624, 2.723]Regression, Logistic
Secondary
Percentage of Seizure-free Participants During the Maintenance Phase
Seizure freedom is defined as no seizures during the Maintenance Phase.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Seizure-free Participants During the Maintenance Phase | 6.0 percentage of participants |
| CVL-865 7.5 mg BID | Percentage of Seizure-free Participants During the Maintenance Phase | 2.2 percentage of participants |
| CVL-865 25 mg BID | Percentage of Seizure-free Participants During the Maintenance Phase | 4.3 percentage of participants |
| CVL-865 7.5 mg BID / 25 mg BID | Percentage of Seizure-free Participants During the Maintenance Phase | 3.2 percentage of participants |
Comparison: CVL-865 25 mg BID vs Placebop-value: >0.999Fisher's exact test
Comparison: CVL-865 7.5 mg BID vs Placebop-value: =0.618Fisher's exact test
Comparison: CVL-865 7.5 mg BID / 25 mg BID vs Placebop-value: =0.422Fisher's exact test
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 | Maintenance Phase Day 15 | 30.99 ng/mL | Standard Deviation 29.086 |
| Placebo | Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 | Maintenance Phase Day 43 | 34.60 ng/mL | Standard Deviation 33.554 |
| Placebo | Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 | Maintenance Phase Day 71 | 32.45 ng/mL | Standard Deviation 29.433 |
| Placebo | Plasma Concentrations of CVL-865 on Maintenance Phase Days 15, 43, and 71, and Taper Phase Day 92 | Taper Phase Day 92 | 9.74 ng/mL | Standard Deviation 14.978 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
| CVL-865 7.5 mg BID | 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 |
Secondary
Weekly Seizure Rate During 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.
Time frame: Maintenance Phase Weeks 1, 2, 3, 4, 5, 6, 7, 8
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 1 | 6.41 Seizures/week | Standard Deviation 10.772 |
| Placebo | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 2 | 5.66 Seizures/week | Standard Deviation 8.858 |
| Placebo | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 3 | 6.81 Seizures/week | Standard Deviation 10.391 |
| Placebo | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 4 | 6.20 Seizures/week | Standard Deviation 8.888 |
| Placebo | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 5 | 5.76 Seizures/week | Standard Deviation 9.269 |
| Placebo | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 6 | 5.44 Seizures/week | Standard Deviation 9.939 |
| Placebo | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 7 | 5.96 Seizures/week | Standard Deviation 9.864 |
| Placebo | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 8 | 6.62 Seizures/week | Standard Deviation 10.797 |
| CVL-865 7.5 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 6 | 6.21 Seizures/week | Standard Deviation 8.313 |
| CVL-865 7.5 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 5 | 6.27 Seizures/week | Standard Deviation 8.688 |
| CVL-865 7.5 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 2 | 4.98 Seizures/week | Standard Deviation 5.982 |
| CVL-865 7.5 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 8 | 5.23 Seizures/week | Standard Deviation 6.883 |
| CVL-865 7.5 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 7 | 6.40 Seizures/week | Standard Deviation 8.52 |
| CVL-865 7.5 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 4 | 6.44 Seizures/week | Standard Deviation 9.974 |
| CVL-865 7.5 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 3 | 6.53 Seizures/week | Standard Deviation 9.01 |
| CVL-865 7.5 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 1 | 5.20 Seizures/week | Standard Deviation 5.867 |
| CVL-865 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 7 | 4.65 Seizures/week | Standard Deviation 8.235 |
| CVL-865 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 3 | 3.26 Seizures/week | Standard Deviation 5.018 |
| CVL-865 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 4 | 3.29 Seizures/week | Standard Deviation 5.13 |
| CVL-865 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 5 | 3.21 Seizures/week | Standard Deviation 6.111 |
| CVL-865 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 6 | 3.29 Seizures/week | Standard Deviation 6.07 |
| CVL-865 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 8 | 3.60 Seizures/week | Standard Deviation 7.063 |
| CVL-865 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 1 | 2.71 Seizures/week | Standard Deviation 4.804 |
| CVL-865 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 2 | 2.74 Seizures/week | Standard Deviation 4.506 |
| CVL-865 7.5 mg BID / 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 3 | 4.88 Seizures/week | Standard Deviation 7.414 |
| CVL-865 7.5 mg BID / 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 4 | 4.87 Seizures/week | Standard Deviation 8.044 |
| CVL-865 7.5 mg BID / 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 2 | 3.84 Seizures/week | Standard Deviation 5.37 |
| CVL-865 7.5 mg BID / 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 1 | 3.95 Seizures/week | Standard Deviation 5.472 |
| CVL-865 7.5 mg BID / 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 5 | 4.75 Seizures/week | Standard Deviation 7.639 |
| CVL-865 7.5 mg BID / 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 8 | 4.45 Seizures/week | Standard Deviation 6.975 |
| CVL-865 7.5 mg BID / 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 7 | 5.56 Seizures/week | Standard Deviation 8.381 |
| CVL-865 7.5 mg BID / 25 mg BID | Weekly Seizure Rate During the Maintenance Phase | Maintenance Phase Week 6 | 4.79 Seizures/week | Standard Deviation 7.408 |