| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Seizures associated with Dravet syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 assess the long-term safety and tolerability of ZX008. |
|
| E.2.2 | Secondary objectives of the trial |
•To assess the effect of ZX008 relative to the pre-ZX008 baseline on the following effectiveness measures:
-The change in the frequency of convulsive seizures
-The proportion of subjects who achieve a ≥ 40%, ≥ 50%, and ≥ 75% reduction in convulsive seizure frequency
-The longest convulsive seizure-free interval
-The percentage of convulsive seizure-free days
-The non-convulsive seizure frequency
-The convulsive + non-convulsive seizure frequency.
•To estimate the incidence of the following on subjects receiving ZX008:
-Use of rescue medication
-Hospitalization to treat seizures
-Status epilepticus (SE)
•To assess the effect of ZX008 relative to the pre-ZX008 baseline on the
following QoL measures:
-QOLCE score
-PedsQL score
-PedsQL Family Impact module score
-QoL of the parent/caregiver using the standardized measure of health
status (EQ-5D-5L) scale
Please refer to Protocol for complete list of Secondary Objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is aged 2 to 18 years inclusive, as of the day of the core study Screening Visit.
2. Subject has satisfactorily completed the core study in the opinion of the investigator and the Sponsor.
NOTE: Those subjects who do not complete the 12-week Maintenance Period of the core study may, on a case-by-case basis, be eligible for entrance after consideration of the circumstances of the early termination and the potential benefit-risk of continued participation in a ZX008 trial. The decision whether to permit OLE study participation resides solely with the Sponsor, who may consult with the site investigator, the IPCAB and/or the IDSMC.
3. Subject is male or non-pregnant, non-lactating female. Female
subjects of childbearing potential must not be pregnant or breastfeeding.
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, which includes abstinence, while being treated on this study and
for 90 days after the last dose of study drug.
4. Subject has documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs.
5. Subject has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian.
6. Subject has provided assent in accordance with IRB/IEC requirements, if capable.
7. Subject’s caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability.
8. 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).
9. Subjects entering from study ZX008-1504 must be receiving a therapeutically relevant and stable dose of clobazam (CLB), valproic acid (VPA), and STP (Cohort 1 dose regimen 3 and Cohort 2 only) for at least 4 weeks prior to screening and are expected to remain stable throughout the study.
10. Subjects who are >18 to ≤35 years of age at the time of screening
and did not participate in one of the core studies must meet criteria 3 to
7 above and the following criteria below in order to be considered for
participation. Participation is at the discretion of the Sponsor:
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.
f. Meets one of the following 3 confirmatory diagnostic criteria:
i. Emergence of another seizure type, including myoclonic, generalized
tonic-clonic, tonic, atonic, absence and/or focal has developed after the
first seizure type.
ii. 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.
iii. 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.)
g. Subject has been approved for study inclusion by the Epilepsy Study
Consortium.
h. Subject does not have an exclusionary cardiovascular or
cardiopulmonary abnormality based on ECHO, ECG or physical
examination and is approved for entry by the central cardiac reader.
Exclusionary abnormalities include, but are not limited to:
i. Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs
of age
ii. Possible signs of pulmonary hypertension with abnormal or greater
than upper limit of normal values
iii. Evidence of diastolic dysfunction
i. Subject must have had ≥4 convulsive seizures (tonic, tonic atonic,
tonic-clonic, clonic) per 4-week period for past 12 weeks prior to
screening, by parent/guardian report to investigator or investigator
medical notes.
j. 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.
11. Subject's parent/caregiver is willing and able to be compliant with
diary completion, visit schedule and study drug accountability. |
|
| 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 current or past history of cardiovascular or cerebrovascular disease, myocardial infarction or stroke.
3. Subject from one of the core studies with current cardiac valvulopathy or pulmonary hypertension that the investigator, parent, IPCAB, IDSMC, or Sponsor deems clinically significant and warrants discontinuation of study medication.
4. For de novo subjects: possible signs of pulmonary hypertension with
abnormal or greater than upper limit of normal values.
5. 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.
6. Subject is at imminent risk of self-harm or harm to others, in the investigator’s opinion, based on clinical interview and responses provided on the Columbia-Suicide Severity Rating Scale (C-SSRS). Subjects must be excluded if they report suicidal behavior as measured by the C-SSRS Since Last Visit, which includes suicidal ideation with intent and plan (Item #5). If a subject reports suicidal ideation on Item 4 without 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.
7. Subject has a current or past history of glaucoma.
8. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic impairment (elevated liver enzymes <3x upper limited 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.
9. 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, and/or cytochrome P450 (CYP) 2D6/3A4/2B6 inhibitors/substrates (see Appendix 1 of the protocol). (Note: Short-term medication requirements will be handled on a per case basis by the Medical Monitor.)
10. Subject is currently taking carbamazepine, oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days, as maintenance therapy.
11. For subjects entering from core studies ZX008-1501, ZX008-1502, or ZX008-1504 (Cohort 1/dose regimens 1 &2): Subject is currently receiving or has received stiripentol in the past 21 days prior to core study Visit 1.
12. Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville oranges, and their juices beginning with Visit 1 and throughout the study.
13. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at Visit 1.
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 Visit 1, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject, including chronic obstructive pulmonary disease, interstitial lung disease, or portal hypertension.
16. Subject has participated in another clinical trial within the past 30
days (ie, the last visit of the previous study was in the past 30 days),
with the exception of one of the core studies. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The effectiveness endpoints of the study are:
•Number of seizures by type
•Convulsive seizure-free interval
•CGI-I as assessed by parent/caregiver
•CGI-I 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 parent/caregiver using the EQ-5D-5L scale
•Affective symptoms of parent/caregiver using the HADS (in parents/caregivers from core studies ZX008-1501 and ZX008-1502 only)
•Duration of prolonged seizures (seizure type that, during pre-Z008 baseline, had duration > 2 minutes)
•Number of episodes of SE
•Number of instances of rescue medication use and number of doses
•Number of inpatient hospital admissions due to seizures
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please refer to study protocol |
|
| E.5.2 | Secondary end point(s) |
The safety endpoints of the study are:
•AEs
•Laboratory safety (hematology, chemistry, urinalysis)
•Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
•Physical examination
•Neurological examination
•12-lead electrocardiogram (ECGs)
•Doppler echocardiogram (ECHOs)
•Body weight
•Behavior Rating Inventory for Executive Function (BRIEF) to measure cognition.
For subjects from core study ZX008-1504 only, the exploratory endpoints of this study are:
•Health and social care resource use, including GP visits, speech and language, occupational and physical therapy, in addition to acute hospital and institutional length of stay, loss of work, etc
•Sleep quality
•Mealtime behavior
•Karolinska Sleepiness Scale to measure the effect of study medication on sleepiness |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to study protocol |
|
| 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 | No |
| 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 | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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