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

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.

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.

Seizure freedom is defined as no seizures 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.

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.

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.

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.

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.

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.

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.

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

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.

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

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).

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.

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

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