|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|Diseases [C] - Nervous System Diseases [C10]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as adjunctive therapy in the treatment 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).
|Secondary objectives of the trial
|• To demonstrate that ZX008 0.2 mg/kg/day is superior to placebo as adjunctive therapy in the treatment of Dravet syndrome based on change in the frequency of convulsive seizures between baseline and T+M.
• To demonstrate that the ZX008 0.2 and 0.8 mg/kg/day dose groups are (independently) 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.
Please refer to the Clinical Study Protocol, Section 2 Study Objectives and Endpoints for complete list of Secondary Endpoints
|Trial contains a sub-study
|Principal 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 of the study protocol), which includes abstinence, while being treated on this study and for 90 days after the last 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, tonic-atonic, clonic) per 4-week period for past 12 weeks prior to screening, by parent/guardian report to investigator or investigator medical notes.
6. All medications or interventions for epilepsy (including KD and VNS) must be stable for at least 4 weeks prior to screening and are expected to remain stable throughout the study.
7. Subject has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian.
8. Subject has provided assent in accordance with Institutional Review Board (IRB) requirements, if capable.
9. Subject’s parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.
RANDOMIZATION INCLUSION CRITERIA
Subjects must meet all of the inclusion criteria above plus the following criteria, to be randomized:
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium.
2. Subject does not have a cardiovascular or cardiopulmonary abnormality based on ECHO, ECG or physical examination, including but not limited to trace mitral or aortic, valve regurgitation or signs of pulmonary hypertension, and is approved for entry by the central cardiac reader.
3. Subject demonstrates a stable baseline with ≥6 convulsive seizures during the 6-week Baseline Period, with a minimum of 2 in the first 3 weeks and 2 in the second three weeks.
4. Subject’s parent/caregiver has been compliant with diary completion during the Baseline Period, in the opinion of the investigator (eg, at least 90% compliant).
|Principal 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 is at imminent risk of self-harm or harm to others, in the investigator’s opinion, based on clinical interview and/or responses provided on the C-SSRS. Subjects must be excluded if they report suicidal behavior in the past 6 months as measured by the C-SSRS at Screening or Baseline, which includes suicidal ideation with intent and plan (Item #5). If a subject reports suicidal ideation on Item 4 without a specific plan, and the investigator feels that the subject is appropriate for the study considering the potential risks, the investigator must document appropriateness for inclusion, and discuss with the parent/caregiver to be alert to mood or behavioral changes, especially around times of dose adjustment.
6. Subject has a current or past history of glaucoma.
7. Subjects with moderate or severe hepatic impairment may not be entered. Asymptomatic subjects with mild hepatic impairment (elevated liver enzymes < 3xULN and/or elevated bilirubin <2xULN) may be entered into the study after review and approval by the Medical Monitor in conjunction with the sponsor, with consideration of potential cause, concomitant medications, and other risk factors.
8. 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; atomoxetine, or other centrally-acting noradrenergic agonist; cyproheptadine (see Appendix 1 of the study protocol). (Note: Short-term medication requirements will be handled on a per case basis by the Medical Monitor.)
9. Subject is currently receiving or has received stiripentol in the past 21 days prior to Screening.
10. Subject is currently taking carbamazepine, oxcarbamazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
11. 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.
12. Subject has positive result on urine THC Panel or whole blood CBD at the Screening Visit.
13. Subject has participated in another clinical trial within the past 30 days.
14. Subject is currently receiving an investigational product.
15. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
16. 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.
|E.5 End points
|Primary end point(s)
• Number of seizures by type
• Convulsive seizure-free interval
• Clinical Global Impression – Improvement as assessed by parent/caregiver
• Clinical Global Impression – Improvement as assessed by principal investigator
• QOLCE to measure changes in quality of life of the subject
• PedsQL to measure changes in quality of life of the subject
• PedsQL Family Impact module to measure changes in quality of life of the parent/caregiver
• QoL of the parent/caregiver using the EQ-5D-5L scale
• Affective symptoms of the parent/caregiver using the HADS scale
• Duration of prolonged seizures (seizure type that, during baseline, had duration >2 minutes)
• Number of episodes of status epilepticus
• Number of instances of rescue medication use and number of doses
• Number of inpatient hospital admissions due to seizures
The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) per 28 days during the T+M periods compared
• Laboratory safety (hematology, chemistry, urinalysis)
• Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
• Physical examination
• Neurological examination
• 12-lead ECGs
• Doppler ECHOs
• Body weight
• BRIEF to measure cognition
• Steady-state plasma fenfluramine PK parameters (Cmax, AUC0-t, Tmax, and t1/2) after administration of ZX008 derived using population PK methods
|Timepoint(s) of evaluation of this end point
|During the course of the study
|Secondary end point(s)
|o The proportion of subjects who achieve a ≥40% reduction from baseline in convulsive seizure frequency.
o The proportion of subjects who achieve a ≥50% reduction from baseline in convulsive seizure frequency.
o The longest convulsive seizure-free interval.
|Timepoint(s) of evaluation of this end point
|Over the Titration and Maintenance (T+M) periods.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days