Seizures
Conditions
Keywords
CVL-865, Anti-epileptic drugs (AEDs), PF-06372865, γ-aminobutyric acid (GABA), focal epilepsy, partial seizure
Brief summary
The purpose of this study is to assess the long-term safety and tolerability of CVL-865 as adjunctive therapy in participants with focal onset seizures.
Interventions
DRUGCVL-865
Participants will receive 25 mg CVL-865 tablets orally BID during the treatment period. The dose may be decreased to 17.5 mg BID for tolerability.
Sponsors
AbbVie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participants who completed treatment in Trial CVL-865-SZ-001 (NCT04244175) * A female participant of childbearing potential who is sexually active with a nonsterilized male partner must agree to use a highly effective method of contraception from signing of informed consent through 30 days post last dose * A male participant with a pregnant or a nonpregnant partner of childbearing potential must agree to use a condom during treatment and until the end of relevant systemic exposure in the male participant for 94 days following the last dose with the investigational medicinal product (IMP) * Participants who are capable of giving signed informed consent * Participants who are able, in the opinion of the investigator, to understand the nature of the trial and comply with protocol requirements, including the prescribed dosage regimens, scheduled visits, laboratory tests, and other trial procedures
Exclusion criteria
* Participants who, in the opinion of the investigator, medical monitor, or sponsor, should not participate in the trial * Participants who, in the judgment of the investigator, experienced poor tolerability to the IMP during the double-blind trial or whose safety assessments resulted in new concerns that would suggest that the participant may not be appropriate for 57 weeks of treatment with CVL-865 in an extension trial * Participants who experienced status epilepticus during Trial CVL-865-SZ-001 * Participants who have demonstrated substantial noncompliance to trial procedures in Trial CVL-865-SZ-001, based on the investigator's judgment, would not be eligible for this trial * Participants who answer yes on the C-SSRS Suicidal Ideation Item 4 or Item 5 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan, or Active Suicidal Ideation with Specific Plan and Intent), or participants who answer yes on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behavior), or participants who, in the opinion of the investigator, present a serious risk of suicide * Participants with any of the following abnormalities in clinical laboratory tests at Visit 1, as assessed by the central laboratory and confirmed by a single repeat measurement, if deemed necessary (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) * Participants who would be likely to require the use of prohibited concomitant medications during the trial * Female participants who have a positive pregnancy test result
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | From first dose of study drug up to Week 61 | A TEAE was defined as an AE that started after the first dose of IMP in the open-label trial or a previously reported AE that increased in intensity, became serious, trial drug-related, or resulted in death, discontinuation, interruption, of reduction of IMP after the first dose of IMP in the open-label trial. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of serious and non-serious AEs regardless of causality is located in the 'Reported Adverse Events module'. |
| Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECGs) | Baseline up to Week 57 | 12-lead ECGs recordings were obtained after the participant had been supine and at rest for at least 5 minutes. The number of participants with significant abnormalities is reported by 'change from baseline in QT interval as corrected for heart rate by Fridericia's formula (QTcF)'. |
| Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Measurements | Baseline up to Week 57 | 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, and heart rate. |
| Number of Participants With Clinically Significant Changes From Baseline in Physical and Neurological Examination Results | Baseline up to Week 57 | A complete physical examination consisted of measurement of weight and a review of the following body systems: head, ears, eyes, nose, mouth, skin, heart, lungs, lymph nodes, and gastrointestinal, genitourinary, and musculoskeletal systems. A full neurological examination included an assessment of the participant's mental status (level of consciousness, orientation, speech, memory, etc), cranial nerves, motor (muscle appearance, tone, strength, and reflexes), sensation (including Romberg sign), coordination, and gait. Reported here is the number of participants with clinically significant changes in physical or neurological examination results. |
| Suicidality Based on the Columbia Suicide-Severity Rating Scale (C-SSRS) | Baseline up to Week 61 | 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 From End of Treatment in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) Score at the End of Post-treatment Follow-up (Week 61) | Week 57, Week 61 | 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 benzodiazepine withdrawal symptoms such as irritability, fatigue, appetite, and sleeplessness. The total score ranges from 1 (no withdrawal) to 68 (extreme withdrawal) with higher scores indicating more severe withdrawal. |
Countries
Australia, Poland, Serbia, South Korea, Spain, Ukraine, United States
Participant flow
Pre-assignment details
Enrollment into the trial consisted of eligible participants who completed the Maintenance Phase of Trial CVL-865-SZ-001 (NCT04244175).
Participants by arm
| Arm | Count |
|---|---|
| CVL-865 25 mg Participants received 25 mg CVL-865 tablets orally BID. | 105 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 9 |
| Overall Study | Death | 1 |
| Overall Study | Lack of Efficacy | 25 |
| Overall Study | Other than specified | 1 |
| Overall Study | Study Terminated by Sponsor | 14 |
| Overall Study | Treatment with Prohibited Concomitant Medications | 1 |
| Overall Study | Withdrawal by Subject | 15 |
Baseline characteristics
| Characteristic | CVL-865 25 mg |
|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 12.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 87 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 90 Participants |
| Sex: Female, Male Female | 55 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 105 |
| other Total, other adverse events | 77 / 105 |
| serious Total, serious adverse events | 11 / 105 |
Outcome results
Primary
Change From End of Treatment in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) Score at the End of Post-treatment Follow-up (Week 61)
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 benzodiazepine withdrawal symptoms such as irritability, fatigue, appetite, and sleeplessness. The total score ranges from 1 (no withdrawal) to 68 (extreme withdrawal) with higher scores indicating more severe withdrawal.
Time frame: Week 57, Week 61
Population: The Safety Set included all participants who received at least 1 dose of IMP. Here, Overall Number of Participants Analyzed is the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CVL-865 25 mg | Change From End of Treatment in Modified Clinical Institute Withdrawal Assessment - Benzodiazepines (mCIWA-B) Score at the End of Post-treatment Follow-up (Week 61) | -1.4 score on a scale | Standard Deviation 8.45 |
Primary
Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECGs)
12-lead ECGs recordings were obtained after the participant had been supine and at rest for at least 5 minutes. The number of participants with significant abnormalities is reported by 'change from baseline in QT interval as corrected for heart rate by Fridericia's formula (QTcF)'.
Time frame: Baseline up to Week 57
Population: The Safety Set included all participants who received at least 1 dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CVL-865 25 mg | Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECGs) | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes From Baseline in Physical and Neurological Examination Results
A complete physical examination consisted of measurement of weight and a review of the following body systems: head, ears, eyes, nose, mouth, skin, heart, lungs, lymph nodes, and gastrointestinal, genitourinary, and musculoskeletal systems. A full neurological examination included an assessment of the participant's mental status (level of consciousness, orientation, speech, memory, etc), cranial nerves, motor (muscle appearance, tone, strength, and reflexes), sensation (including Romberg sign), coordination, and gait. Reported here is the number of participants with clinically significant changes in physical or neurological examination results.
Time frame: Baseline up to Week 57
Population: The Safety Set included all participants who received at least 1 dose of IMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CVL-865 25 mg | Number of Participants With Clinically Significant Changes From Baseline in Physical and Neurological Examination Results | Number of participants with any clinically significant physical examination findings | 5 Participants |
| CVL-865 25 mg | Number of Participants With Clinically Significant Changes From Baseline in Physical and Neurological Examination Results | Number of participants with any clinically significant neurological examination findings | 7 Participants |
Primary
Number of Participants With Clinically Significant Changes From Baseline 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, and heart rate.
Time frame: Baseline up to Week 57
Population: The Safety Set included all participants who received at least 1 dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CVL-865 25 mg | Number of Participants With Clinically Significant Changes From Baseline in Vital Sign Measurements | 2 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
A TEAE was defined as an AE that started after the first dose of IMP in the open-label trial or a previously reported AE that increased in intensity, became serious, trial drug-related, or resulted in death, discontinuation, interruption, of reduction of IMP after the first dose of IMP in the open-label trial. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of serious and non-serious AEs regardless of causality is located in the 'Reported Adverse Events module'.
Time frame: From first dose of study drug up to Week 61
Population: The Safety Set included all participants who received at least 1 dose of IMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CVL-865 25 mg | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Participants with TEAE | 88 Participants |
| CVL-865 25 mg | Number of Participants With Treatment Emergent Adverse Event (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Participants with TESAE | 11 Participants |
Primary
Suicidality Based on the 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: Baseline up to Week 61
Population: The Safety Set included all participants who received at least 1 dose of IMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CVL-865 25 mg | Suicidality Based on the Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (1) Wish to be dead | 6 Participants |
| CVL-865 25 mg | Suicidality Based on the Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (2) Non-specific active suicidal thoughts | 5 Participants |
| CVL-865 25 mg | Suicidality Based on the 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 | Suicidality Based on the Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (4) Active suicidal ideation with some intent to act, without specific plan | 2 Participants |
| CVL-865 25 mg | Suicidality Based on the Columbia Suicide-Severity Rating Scale (C-SSRS) | Suicidal Ideation: (5) Active suicidal ideation with specific plan and intent | 0 Participants |