Dravet's syndrome MedDRA version: 18.1 Level: LLT Classification code 10073682 Term: Dravet syndrome System Organ Class: 100000004850
Conditions
Interventions
Product Name: Fenfluramine hydrochloride
Product Code: ZX008
Pharmaceutical Form: Oral solution
INN or Proposed INN: FENFLURAMINE HYDROCHLORIDE
CAS Number: 404-82-0
Concentration unit: mg/ml milligram
Sponsors
Zogenix International Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the Screening Visit. Female subjects of childbearing potential must not be pregnant or breast-feeding. Female subjects of childbearing potential must have a negative urine pregnancy test. Subjects of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control (see Section 4.4), which includes abstinence, while being treated on this study and for 90 days after the dose of study drug. 2. 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. 3. Subjects must meet all of the following 5 criteria: a. Onset of seizures in the first year of life in an otherwise healthy infant. b. A history of seizures that are either generalized tonic-clonic or unilateral clonic or bilateral clonic, and are prolonged. c. Initial development is normal. d. History of normal brain MRI without cortical brain malformation. e. Lack of alternative diagnosis. 4. Subjects must meet at least one of the following 3 criteria: a. Emergence of another seizure type, including myoclonic, generalized tonic-clonic, tonic, atonic, absence and/or focal has developed after the first seizure type. b. Prolonged exposure to warm temperatures induces seizures and/or seizures are associated with fevers due to illness or vaccines, hot baths, high levels of activity and sudden temperature changes and/or seizures are induced by strong natural and/or fluorescent lighting, as well as certain visual patterns. c. Genetic test results consistent with a diagnosis of Dravet syndrome (pathogenic, likely pathogenic, variant of unknown significance, or inconclusive but unlikely to support an alternative diagnosis.) 5. Subject must have had =4 convulsive seizures (tonic-clonic, tonic, atonic, clonic) per 4-week period for past 12 weeks prior to screening, by parent/guardian report to investigator or investigator medical notes [Cohort 2 only]. 6. All medications or interventions for epilepsy (including ketogenic diet [KD] and vagal nerve stimulation [VNS]) must be stable for at least 4 weeks prior to screening and are expected to remain stable throughout the study. 7. Subject must be receiving a therapeutically relevant and stable dose of CLB, VPA, and STP for at least 4 weeks prior to screening and are expected to remain stable throughout the study [Cohort 2 only]. 8. Subject must be receiving a stable dose of CLB and VPA, administered twice daily, to be eligible for Dose Regimen 1 and 2 or subject must be receiving a stable dose of CLB, VPA, and STP, administered twice daily, to be eligible for Dose Regimen 3 [Cohort 1 only]. 9. Subject agrees to provide whole blood sample for a broad epilepsy-related gene testing panel. 10. Subject agrees to provide a buccal swab for CYP2D6 genotyping. 11. Subject has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian. 12. Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics Committee requirements, if capable. 13. Subject’s parent/caregiver is willing and able to be compliant with all study requirements and visit schedule. Subject’s parent/caregiver must also be willing and able to be compliant with diary completion and study drug accountability [Coho
Exclusion criteria
Exclusion criteria: 1. Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication. 2. Subject has pulmonary arterial hypertension. 3. Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke. 4. Subject has 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. 5. Subject has a current or past history of glaucoma. 6. Subject has moderate or severe hepatic impairment. a. Asymptomatic subjects with mild hepatic impairment (asparate aminotransferase [AST] and alanine aminotransferase [ALT] < 2x the upper limit of normal (ULN) and no elevations of gamma-glutamyltransferase [GGT], alkaline phosphatase, or total bilirubin indicative of more than mild hepatic impairment), may be entered into the study after review and approval by the Medical Monitor in conjunction with the sponsor, in consideration of comorbidities and concomitant medications [Cohort 1 only]. b. Asymptomatic subjects with mild hepatic impairment (elevated liver enzymes <3x the upper limit of normal [ULN] and/or elevated bilirubin <2x ULN) may be entered into the study after review and approval by the Medical Monitor in conjunction with the sponsor, in consideration of comorbidities and concomitant medications [Cohort 2 only]. 7. 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 agonist; cyproheptadine, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates (see Appendix 1). (Note: Short-term medication requirements will be handled on a per case basis by the Medical Monitor.) 8. Subject is currently receiving or has received STP in the past 21 days prior to Screening [only for Cohort 1 subjects allocated to Dose Regimen 1 or 2]. 9. Subject is currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days as maintenance therapy. 10. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville oranges, and their juices beginning with the Baseline Period and throughout the study. 11. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at the Screening Visit. 12. Subject has participated in another clinical trial within the past 30 days. 13. Subject is currently receiving an investigational product. 14. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. 15. 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 |
|---|---|
| Main Objective: To demonstrate that ZX008 is superior to placebo as adjunctive therapy in the treatment of symptoms of Dravet syndrome in children and young adults based on change in the frequency of convulsive seizures between baseline and the combined Titration and Maintenance Periods (T+M) in Cohort 2.;Secondary Objective: To demonstrate that ZX008 is superior to placebo on the following endpoints: - The proportion of subjects who achieve a =40% reduction from baseline in convulsive seizure frequency. - The proportion of subjects who achieve a =50% reduction from baseline in convulsive seizure frequency. - The longest convulsive seizure-free interval. ;Primary end point(s): The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) per 28 days between the Baseline and T+M periods;Timepoint(s) of evaluation of this end point: The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) per 28 days between the Baseline and T+M periods | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The first key secondary endpoint is the proportion of subjects who achieve a =40% reduction from baseline in convulsive seizure frequency ;Timepoint(s) of evaluation of this end point: The longest interval between convulsive seizures will be calculated for each subject over the entire T+M period | — |
Countries
Germany, Netherlands, Spain, United Kingdom
Contacts
Public ContactArun Mistry
Zogenix International Limited
Outcome results
None listed