| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073682 |
| E.1.2 | Term | Dravet syndrome |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
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| E.2.2 | Secondary objectives of the trial |
The key secondary efficacy objectives of the study are related to Cohort 2 and include:
To demonstrate that ZX008 is superior to placebo on the following endpoints:
- The proportion of subjects who achieve a ≥50% reduction from baseline in convulsive seizure frequency.
- The longest convulsive seizure-free interval.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | 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), 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 (AEDs).
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 magnetic resonance imaging (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, 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]. (In some cases, subjects who are contraindicated for VPA or CLB may be enrolled in Cohort 2. Subjects in these cases must be receiving a therapeutically relevant and stable dose of STP and VPA [if contraindicated for CLB] or STP and CLB [if contraindicated for VPA].
8.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].
9.Subject agrees to provide a buccal swab for CYP2D6 (cytochrome P450 2D6) genotyping.
10.Subject has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian.
11.Subject has provided assent in accordance with Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements, if capable.
12.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.
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| E.4 | 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 has a current or past history of glaucoma.
6.Subject has moderate or severe hepatic impairment.
a.Asymptomatic subjects with mild hepatic impairment (aspartate 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 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; or cyproheptadine (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, oxcarbazepine, 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.
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| E.5 End points |
| E.5.1 | 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 |
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| E.5.1.1 | 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 |
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| E.5.2 | Secondary end point(s) |
| The first key secondary endpoint is the proportion of subjects who achieve a ≥50% reduction from baseline in convulsive seizure frequency |
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| E.5.2.1 | 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 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Cohort 1 = open with 3 treatment arms; Cohort 2 = double blind, controlled, with 2 treatment arms |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Germany |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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