Dravet Syndrome
Conditions
Keywords
Seizure, Tonic clonic, Epilepsy, Myoclonic, Encephalopathy
Brief summary
The primary purpose of this study is to evaluate the safety, tolerability, and efficacy of ZX008 (fenfluramine hydrochloride) when added to adjunctive antiepileptic stiripentol treatment in children and young adults with Dravet syndrome.
Detailed description
This is a multicenter, 2-cohort trial to first assess the pharmacokinetic and safety profile of a single dose of ZX008 (fenfluramine hydrochloride) oral solution when added to a standard Dravet syndrome treatment regimen containing valproate (VPA) and clobazam (CLB), with or without stiripentol (STP) (Cohort 1), followed by a randomized, double-blind, placebo-controlled parallel group evaluation of the efficacy, safety, and tolerability of ZX008 as adjunctive therapy for seizures in children and young adults with Dravet syndrome (Cohort 2).
Interventions
ZX008 0.5 mg/kg/day (maximum 20 mg/day). ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL. \*Note: The 0.5 mg/kg/day dose of ZX008 fenfluramine hydrochloride in this study is equivalent to 0.4 mg/kg/day (maximum 17 mg/day) dose of fenfluramine base.
DRUGMatching Placebo
Matching Placebo
Sponsors
Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subject must be male or non-pregnant, non-lactating female, aged 2 to 18 years (inclusive). * Subject must have documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs. * Subject must be receiving a therapeutically relevant and stable dose of stiripentol (STP) plus clobazam (CLB) and/or valproate (VPA), and for at least 4 weeks prior to screening and be expected to remain stable throughout the study (Cohort 2 only). * Subject must be receiving a stable dose of CLB and VPA, administered twice daily (BID), to be eligible for Dose Regimen 1 and 2, or subject must be receiving a stable dose of CLB, VPA, and STP, administered BID, to be eligible for Dose Regimen 3 (Cohort 1 only). Key
Exclusion criteria
* Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication. * Subject has pulmonary arterial hypertension. * Subject has a current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction, or stroke. * Subject has a current or recent history of anorexia nervosa, bulimia, or depression within the prior year that required medical treatment or psychological treatment for a duration greater than 1 month. * Subject has a current or past history of glaucoma. * Subject is receiving concomitant therapy with: centrally acting anorectic agents; monoamine-oxidase inhibitors; any centrally acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; triptans, atomoxetine, or other centrally acting noradrenergic agonists; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates. * Subject is currently taking carbamazepine ,oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy. * Subject has a positive result on urine tetrahydrocannabinol (THC) panel or whole blood cannabidiol (CBD) at the Screening Visit. * Subject has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to the Screening Visit, 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 |
|---|---|---|
| Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period | 15 weeks (combined Titration + Maintenance Period) | Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period | 15 weeks (combined Titration + Maintenance Period) | Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups. |
| Longest Convulsive Seizure-Free Interval (Days) | 15 weeks (combined Titration + Maintenance Period) | Comparison of the duration of the longest convulsive seizure-free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups. |
Countries
Canada, France, Germany, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 28 study sites in Canada, France, Germany, the Netherlands, Spain, the United Kingdom, and the United States enrolled participants for Study 1504 Cohort 2.
Pre-assignment details
A total of 115 subjects were screened for eligibility to participate in Study 1504 Cohort 2. Of these, 87 subjects were enrolled and randomized.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 2: ZX008 0.5 mg/kg/Day ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose administered twice a day (BID) in equally divided doses. | 43 |
| Cohort 2: Matching Placebo Matching placebo administered twice a day (BID) in equally divided doses. | 44 |
| Total | 87 |
Baseline characteristics
| Characteristic | Cohort 2: ZX008 0.5 mg/kg/Day | Total | Cohort 2: Matching Placebo |
|---|---|---|---|
| Age, Continuous Cohort 2 | 8.8 years STANDARD_DEVIATION 4.56 | 9.1 years STANDARD_DEVIATION 4.8 | 9.4 years STANDARD_DEVIATION 5.05 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 10 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 47 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 30 Participants | 15 Participants |
| Race (NIH/OMB) Cohort 2 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort 2 Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Cohort 2 Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Cohort 2 More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort 2 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Cohort 2 Unknown or Not Reported | 17 Participants | 29 Participants | 12 Participants |
| Race (NIH/OMB) Cohort 2 White | 23 Participants | 52 Participants | 29 Participants |
| Region of Enrollment Canada | 4 Participants | 7 Participants | 3 Participants |
| Region of Enrollment France | 13 Participants | 23 Participants | 10 Participants |
| Region of Enrollment Germany | 0 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Netherlands | 8 Participants | 10 Participants | 2 Participants |
| Region of Enrollment Spain | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 12 Participants | 9 Participants |
| Region of Enrollment United States | 11 Participants | 22 Participants | 11 Participants |
| Sex: Female, Male Cohort 2 Female | 20 Participants | 37 Participants | 17 Participants |
| Sex: Female, Male Cohort 2 Male | 23 Participants | 50 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 44 |
| other Total, other adverse events | 42 / 43 | 42 / 44 |
| serious Total, serious adverse events | 6 / 43 | 7 / 44 |
Outcome results
Primary
Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period
Monthly (28 day) convulsive seizure frequency (CSF) was based on electronic diary data obtained for each participant. Convulsive seizures included hemiclonic, focal with clear observable motor signs, generalized tonic clonic, secondarily generalized tonic clonic, tonic, clonic, and drop seizures (tonic/atonic). The number of convulsive seizures reported during the entire time interval was divided by the number of nonmissing diary days and the result was then multiplied by 28 to get a 28-day CSF.
Time frame: 15 weeks (combined Titration + Maintenance Period)
Population: Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 2: ZX008 0.5 mg/kg/Day | Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period | -3.18 Convulsive seizures per 28 days | Standard Deviation 44.121 |
| Cohort 2: Matching Placebo | Change in Convulsive Seizure Frequency (CSF) From the Baseline Period (Baseline) to the Combined Titration + Maintenance (T+M) Period | -0.65 Convulsive seizures per 28 days | Standard Deviation 8.767 |
p-value: <0.00195% CI: [-67.2, -35.6]ANCOVA
Secondary
Longest Convulsive Seizure-Free Interval (Days)
Comparison of the duration of the longest convulsive seizure-free interval (days) during the combined Titration + Maintenance Periods for the ZX008 0.5 mg/kg/day and placebo groups.
Time frame: 15 weeks (combined Titration + Maintenance Period)
Population: Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2: ZX008 0.5 mg/kg/Day | Longest Convulsive Seizure-Free Interval (Days) | 22.0 Days |
| Cohort 2: Matching Placebo | Longest Convulsive Seizure-Free Interval (Days) | 13.0 Days |
p-value: 0.004Wilcoxon (Mann-Whitney)
Secondary
Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period
Percentage of participants who achieved ≥ a 50% reduction in convulsive seizure frequency from Baseline compared to the combined Titration + Maintenance Periods in the ZX008 0.5 mg/kg/day vs placebo groups.
Time frame: 15 weeks (combined Titration + Maintenance Period)
Population: Modified intent-to-treat (mITT) Population, defined as all randomized subjects who received at least 1 dose of ZX008 or placebo and for whom at least 1 week of diary data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 2: ZX008 0.5 mg/kg/Day | Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period | 53.5 Percentage of participants |
| Cohort 2: Matching Placebo | Percentage of Participants Who Achieved ≥ a 50% Reduction in Convulsive Seizure Frequency From Baseline to the Combined Titration + Maintenance Period | 4.5 Percentage of participants |
p-value: <0.001Regression, Logistic