Dravet Syndrome
Conditions
Keywords
seizure, tonic clonic, epilepsy, myoclonic, encephalopathy
Brief summary
This is an international, multicenter, open-label, long-term safety study of ZX008 in subjects with Dravet syndrome.
Detailed description
This is an international, multicenter, open-label, long-term safety study of ZX008 in pediatric and young adult subjects with Dravet syndrome who participated in one of the core studies (ZX008-1501 and ZX008-1502) and are candidates for continuous treatment for an extended period of time. This trial will consist of a 36-month Open-Label Extension (OLE) Treatment Period and a 2-week Post-Dosing Period.
Interventions
Sponsors
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the core study Screening Visit. * Satisfactory completion of the core study in the opinion of the investigator and the sponsor. * Subjects who are \>18 to ≤35 years of age at the time of screening and did not participate in one of the core studies may be eligible for participation. * A documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs. * Parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability. * Subject's parent/caregiver has been compliant with diary completion during the core study, in the opinion of the investigator (eg, at least 90% compliant). Key
Exclusion criteria
* Current or past history of cardiovascular or cerebrovascular disease, myocardial infarction or stroke. * Current cardiac valvulopathy or pulmonary hypertension that is clinically significant and warrants discontinuation of study medication. * Current or past history of glaucoma. * Moderate or severe hepatic impairment. * Receiving concomitant therapy with: centrally-acting anorectic agents; monoamineoxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates. * Currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy. * A clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness at Visit 1, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Open-label Extension (OLE) Treatment Period | From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42) | Treatment-emergent adverse events (TEAE) were defined as any AEs that based on start date information occurs after the first intake of study treatment. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Withdrawal From Investigational Medicinal Product (IMP) During the OLE Treatment Period | From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42) | A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. Percentage of participants with TEAEs leading to withdrawal from IMP during OLE Treatment Period were reported. |
| Percentage of Participants With Serious Treatment-emergent Adverse Events (TEAEs) During the OLE Treatment Period | From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42) | Serious Adverse event (SAE) was defined as any untoward medical occurrence that at any dose: • results in death, • is life-threatening threatening, • results in initial inpatient hospitalization or prolongation of hospitalization, •results in persistent or significant disability or incapacity, • results in a congenital anomaly/birth defect, • results in any medically significant event that did not meet any of the other 5 SAE criteria, but which was judged by a physician to potentially jeopardize the participant or require medical or surgical intervention to prevent one of the above outcomes listed as an SAE criterion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period | From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42) | Convulsive seizure frequency over time, reported as per 28 days was analyzed by the actual dose administered. Participants were grouped into low (0.2 to \<0.4 mg/kg), medium (0.4 to \<0.6 mg/kg), and high dose (\>0.6 mg/kg) groups depending on their mean daily doses of ZX008 during the OLE Treatment period. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The convulsive seizure frequency was calculated from all available data collected. |
| Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period | From Day 1 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core) | Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies (ZX008-1501/ZX008-1502, and ZX008-1504 Cohort 2). Participants in 1504- Cohort 1 and de novo participants (who entered 1503 without having been in any of the core studies) did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Day 1 to EOS was divided by the total number of days from Day 1 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day convulsive seizure frequency (CSF). The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant. |
| Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period | At Month 1, 2, 3, 4 , 5, and 6 of OLE Treatment Period | Participants in the study were required to be on stable background therapy for the first 6 months of treatment, after which background AEDs could be reduced or withdrawn so long as one background AED remained. The percentage of participants who had changes in dose or type of concomitant AED medications during the first, second, third, fourth, fifth, and sixth months were analyzed and reported. |
| Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Month 2 to EOS (Month 42) in the OLE Treatment Period | From Month 2 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core) | Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies. Participants in 1504-Cohort 1 and de novo participants did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Month 2 to EOS was divided by the total number of days from Month 2 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF. The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant. |
| Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | At Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 10-12, Month 13-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month 31-33, and Month 34-36 | Monthly (28 day) CSF was based on electronic diary data obtained for each participant. The total number of convulsive seizures in the ith interval (CSF in OLE, where, i=1, 2, 3, … , 14 ) was divided by the total number of days in the ith interval with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF of OLE. |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Italy, Japan, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study started to enroll participants in Jun 2016 and concluded in Jan 2023. Participants who completed 14 weeks treatment in any of the core studies ZX008-1501/ZX008-1502 (NCT02682927), or ZX008-1504 (NCT02926898) Cohort 2, or completed ZX008-1504 Cohort 1 study, and de novo participants were eligible to participate in this study.
Pre-assignment details
The Participant Flow refers to the Safety (SAF) Population.
Participants by arm
| Arm | Count |
|---|---|
| Any ZX008 Open Label Dose Participants received ZX008 0.2 milligram per kilogram per day (mg/kg/day) as an oral solution, twice a day (bid), in equally divided doses with food for 1 month. After 1 month, investigator might have adjusted the dose of each participant based on effectiveness and tolerability. Participants who were not receiving concomitant stiripentol, dose changes should be made in increments of 0.2 mg/kg/day, to a maximum of 0.8 mg/kg/day but not to exceed total dose of 30 mg/day for 42 months of OLE Period. Participants who were receiving concomitant stiripentol, the first dose change was 0.4 mg/kg/day and the final dose change was to 0.5 mg/kg/day, but not to exceed 20 mg/day for 42 months of OLE Period. | 374 |
| Total | 374 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Enrollment | Other | 1 | 0 |
| Treatment | Adverse Event | 0 | 11 |
| Treatment | Death | 0 | 3 |
| Treatment | Family Decision | 0 | 1 |
| Treatment | IP approved and subject moved to commercial drug | 0 | 1 |
| Treatment | Lack of Efficacy | 0 | 48 |
| Treatment | Non-Compliance With E-Diary | 0 | 1 |
| Treatment | Physician Decision | 0 | 2 |
| Treatment | Reason unknown | 0 | 1 |
| Treatment | Subject has transitioned to study 1900 OLE study | 0 | 225 |
| Treatment | Subject needed to take prohibited medication | 0 | 1 |
| Treatment | Subject transferred to direct access programme | 0 | 1 |
| Treatment | Switching to commercially available drug | 0 | 11 |
| Treatment | Transitioned to commercial supply of medication | 0 | 1 |
| Treatment | Withdrawal By Caregiver | 0 | 1 |
| Treatment | Withdrawal by sponsor due to lack of compliance | 0 | 1 |
| Treatment | Withdrawal by Subject | 0 | 16 |
Baseline characteristics
| Characteristic | Any ZX008 Open Label Dose |
|---|---|
| Age, Continuous | 10.3 years STANDARD_DEVIATION 6.12 |
| Age, Customized >18 years | 32 Participants |
| Age, Customized 6-18 years | 250 Participants |
| Age, Customized <6 years | 92 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants |
| Race/Ethnicity, Customized Asian | 31 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 44 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 267 Participants |
| Race/Ethnicity, Customized Not Reported | 44 Participants |
| Race/Ethnicity, Customized Other | 17 Participants |
| Race/Ethnicity, Customized Unknown | 8 Participants |
| Race/Ethnicity, Customized White | 275 Participants |
| Sex: Female, Male Female | 172 Participants |
| Sex: Female, Male Male | 202 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 374 |
| other Total, other adverse events | 342 / 374 |
| serious Total, serious adverse events | 99 / 374 |
Outcome results
Primary
Percentage of Participants With Serious Treatment-emergent Adverse Events (TEAEs) During the OLE Treatment Period
Serious Adverse event (SAE) was defined as any untoward medical occurrence that at any dose: • results in death, • is life-threatening threatening, • results in initial inpatient hospitalization or prolongation of hospitalization, •results in persistent or significant disability or incapacity, • results in a congenital anomaly/birth defect, • results in any medically significant event that did not meet any of the other 5 SAE criteria, but which was judged by a physician to potentially jeopardize the participant or require medical or surgical intervention to prevent one of the above outcomes listed as an SAE criterion.
Time frame: From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)
Population: Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Any ZX008 Open Label Dose | Percentage of Participants With Serious Treatment-emergent Adverse Events (TEAEs) During the OLE Treatment Period | 26.5 percentage of participants |
Primary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Open-label Extension (OLE) Treatment Period
Treatment-emergent adverse events (TEAE) were defined as any AEs that based on start date information occurs after the first intake of study treatment.
Time frame: From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)
Population: Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Any ZX008 Open Label Dose | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Open-label Extension (OLE) Treatment Period | 98.1 percentage of participants |
Primary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Withdrawal From Investigational Medicinal Product (IMP) During the OLE Treatment Period
A TEAE was defined as any AE that based on start date information occurs after the first intake of study treatment. Percentage of participants with TEAEs leading to withdrawal from IMP during OLE Treatment Period were reported.
Time frame: From Day 1 to End of OLE Treatment Period - EOS Visit (Month 42)
Population: Safety (SAF) population included all enrolled participants who received at least one dose of ZX008 during the OLE.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Any ZX008 Open Label Dose | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Withdrawal From Investigational Medicinal Product (IMP) During the OLE Treatment Period | 3.5 percentage of participants |
Secondary
Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period
Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies (ZX008-1501/ZX008-1502, and ZX008-1504 Cohort 2). Participants in 1504- Cohort 1 and de novo participants (who entered 1503 without having been in any of the core studies) did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Day 1 to EOS was divided by the total number of days from Day 1 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day convulsive seizure frequency (CSF). The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant.
Time frame: From Day 1 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)
Population: Modified Intent-to-Treat (mITT) population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Any ZX008 Open Label Dose | Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Day 1 to End of Study (EOS) Visit (Month 42) in the OLE Treatment Period | -6.67 seizure frequency per 28 days |
Secondary
Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Month 2 to EOS (Month 42) in the OLE Treatment Period
Baseline (Core) was defined as Baseline prior to double-blind treatment in the core studies. Participants in 1504-Cohort 1 and de novo participants did not have a Baseline (Core), and were not included in the analysis of this outcome measure. The total number of convulsive seizures from Month 2 to EOS was divided by the total number of days from Month 2 to EOS with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF. The change from Baseline for any individual participant was calculated by subtracting the Baseline (Core) from the post-baseline value. Monthly (28 day) CSF was based on electronic diary data obtained for each participant.
Time frame: From Month 2 to End of OLE Treatment Period (EOS Visit - up to Month 42), compared to Baseline (Core)
Population: mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, number of participants analyzed included those participants who were evaluable for the assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Any ZX008 Open Label Dose | Change From Baseline (Core) in Convulsive Seizure Frequency Per 28 Days From Month 2 to EOS (Month 42) in the OLE Treatment Period | -7.04 seizure frequency per 28 days |
Secondary
Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period
Convulsive seizure frequency over time, reported as per 28 days was analyzed by the actual dose administered. Participants were grouped into low (0.2 to \<0.4 mg/kg), medium (0.4 to \<0.6 mg/kg), and high dose (\>0.6 mg/kg) groups depending on their mean daily doses of ZX008 during the OLE Treatment period. For each participant, the seizure frequency per 28 days was calculated as the number of seizures recorded during the period, divided by the number of days in the period and multiplied by 28. The convulsive seizure frequency was calculated from all available data collected.
Time frame: From Day 1 to End of OLE Treatment Period - End of Study (EOS) Visit (Month 42)
Population: mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, number analyzed represents the number of participants categorized by mean daily dose.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period | ZX008 Low Dose (0 - <0.4 mg/kg/day) | 3.94 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period | ZX008 Medium Dose (0.4 - <0.6 mg/kg/day) | 4.80 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) by Mean Daily Dose During the Overall OLE Treatment Period | ZX008 High Dose (>=0.6 mg/kg/day) | 6.00 seizure frequency per 28 days |
Secondary
Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36)
Monthly (28 day) CSF was based on electronic diary data obtained for each participant. The total number of convulsive seizures in the ith interval (CSF in OLE, where, i=1, 2, 3, … , 14 ) was divided by the total number of days in the ith interval with nonmissing diary data and the result was then multiplied by 28 to get a 28-day CSF of OLE.
Time frame: At Month 1, Month 2, Month 3, Month 4-6, Month 7-9, Month 10-12, Month 13-15, Month 16-18, Month 19-21, Month 22-24, Month 25-27, Month 28-30, Month 31-33, and Month 34-36
Population: mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE. Here, number analyzed signifies participants who were evaluable at specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 34-36 | 2.74 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 1 | 6.53 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 2 | 4.67 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 3 | 4.67 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 4-6 | 4.36 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 7-9 | 3.82 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 10-12 | 4.04 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 13-15 | 3.11 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 16-18 | 3.42 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 19-21 | 3.42 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 22-24 | 2.80 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 25-27 | 2.80 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 28-30 | 2.80 seizure frequency per 28 days |
| Any ZX008 Open Label Dose | Convulsive Seizure Frequency (CSF) Per 28 Days During the OLE Treatment Period (to Month 36) | Month 31-33 | 3.21 seizure frequency per 28 days |
Secondary
Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period
Participants in the study were required to be on stable background therapy for the first 6 months of treatment, after which background AEDs could be reduced or withdrawn so long as one background AED remained. The percentage of participants who had changes in dose or type of concomitant AED medications during the first, second, third, fourth, fifth, and sixth months were analyzed and reported.
Time frame: At Month 1, 2, 3, 4 , 5, and 6 of OLE Treatment Period
Population: mITT population included all enrolled participants who received at least one dose of ZX008 and had at least 1 month of valid seizure data during the OLE.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Any ZX008 Open Label Dose | Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period | OLE Month 6 | 9.6 percentage of participants |
| Any ZX008 Open Label Dose | Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period | OLE Month 1 | 5.2 percentage of participants |
| Any ZX008 Open Label Dose | Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period | OLE Month 2 | 7.1 percentage of participants |
| Any ZX008 Open Label Dose | Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period | OLE Month 3 | 7.4 percentage of participants |
| Any ZX008 Open Label Dose | Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period | OLE Month 4 | 8.3 percentage of participants |
| Any ZX008 Open Label Dose | Percentage of Participants With Changes in Antiepileptic Drug (AED) Medications During First 6 Months of OLE Treatment Period | OLE Month 5 | 6.8 percentage of participants |