| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Lennox-Gastaut Syndrome in Children and Adults |
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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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048816 |
| E.1.2 | Term | Lennox-Gastaut syndrome |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
The primary objective of Part 1 is to evaluate the effect of ZX008 0.8 mg/kg/day versus placebo as adjunctive therapy for the treatment of uncontrolled seizures in children and adults with Lennox-Gastaut syndrome (LGS) based on the change in frequency of seizures that result in drops between baseline and the combined Titration and Maintenance Periods (T+M)
The primary objective of Part 2 is to assess the long-term safety and tolerability of ZX008 in children and adults with LGS with regard to adverse events (AEs), laboratory parameters, physical examination, neurological examination, suicidality, cognition (BRIEF), vital signs (blood pressure, heart rate, temperature, and respiratory rate), chest x-ray, electrocardiograms (ECG), echocardiograms (ECHO), body weight, and BMI.
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| E.2.2 | Secondary objectives of the trial |
The key secondary objectives of Part 1 are:
• Evaluation of effect of ZX008 0.2 mg/kg/day vs placebo as adjunctive therapy for the treatment of uncontrolled seizures in children and adults with LGS based on the change in frequency of seizures that result in drops between baseline and T+M
• Evaluation of effect of ZX008 0.2 and 0.8 mg/kg/day (independently) vs placebo on the endpoints listed in Protocol synopsis.
The secondary objectives of Part 2 are assessment of effect of ZX008 relative to the baseline on the effectiveness measures, and determination of incidence of medical services used to treat seizures; of status epilepticus and of rescue medication. |
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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 35 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 at screening. 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 last dose of study drug.
2.Subject must have a diagnosis of Lennox-Gastaut syndrome, where seizures that result in drops are not completely controlled by current antiepileptic treatments. (Subjects without a formal diagnosis may still be enrolled at sponsor discretion if all other criteria are met.)
3.Subjects must meet all of the following 4 criteria for Lennox-Gastaut syndrome, as defined in this protocol:
a. Onset of seizures at 11 years of age or younger.
b. Multiple seizure types (must include TS or TA), including countable motor seizures that result in drops. Countable motor seizure types eligible for inclusion are: GTC, TS, CS, AS, FS with observable motor symptoms and MS with a drop.
c. Abnormal cognitive development.
d. Evidence of EEG in the medical history that shows abnormal background activity accompanied by slow spike and wave pattern <2.5 Hz. (Acceptable evidence includes a copy of the EEG trace, EEG report, or physician note that appropriately describes the EEG findings.)
4. Subject must have had at least 8 drop seizures in the last 4 weeks prior to inclusion (minimum of 4 drop seizures in the first two weeks and 4 in the last two weeks before baseline), by parent/guardian report to investigator or investigator medical notes
5. Receiving at least 1 concomitant AED and up to 4 concomitant AEDs, inclusive. KD and VNS are permitted but do not count towards the total number of AEDs. Rescue medications for seizures are not counted towards the total number of AEDs.
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)/Ethics Committee 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 and none of the exclusion criteria above and meet the following criteria in order to be randomized:
1. Subject has been approved for study inclusion by the Epilepsy Study Consortium.
2. 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:
a. Trace or greater mitral or aortic valve regurgitation in subjects ≤18 years of age
b. Mild or greater mitral or aortic valve regurgitation in subjects >18 yrs of age
c. Possible signs of pulmonary hypertension with abnormal or greater than upper range of normal values
d. Evidence of left ventricular dysfunction (systolic or diastolic)
3. Subject demonstrates a stable baseline with ≥ 2 seizures per week resulting in drops during the 4-week Baseline Period.
4. Subject’s parent/caregiver has been compliant with diary completion during the Baseline Period, in the opinion of the investigator and sponsor.
Selection Criteria for Part 2
To be included in Part 2 all subjects must continue to meet the Selection Criteria for Part 1 (except for criteria related to seizure frequency). If a subject entering Part 2 does not meet Randomization Criteria 2 regarding cardiovascular abnormalities, Section 8.9.1 Follow-up of Cardiovascular Findings will be applied to determine eligibility to continue into Part 2.
1. All subjects must have satisfactorily completed Part 1 of the study in the opinion of the investigator and the sponsor.
2. Those subjects who do not complete the 12-week Maintenance Period of Part 1 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 participation in Part 2 for subjects who do not complete Part 1 resides solely with the sponsor, who may consult with the site investigator, the ICAB and/or the IDSMC.
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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’s etiology of seizures is a degenerative neurological disease.
3. Subject has a history of hemiclonic seizures in the first year of life.
4. Subject only has drop seizures in clusters, where individual seizures cannot be counted reliably.
5. Subject has pulmonary arterial hypertension.
6. Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke, or clinically significant structural cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular septal defects, patent ductus arteriosis (note: Patent Foramen Ovale or a bicuspid valve are not considered exclusionary).
7. 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.
8. Subject has a current or past history of glaucoma.
9. Subject has had an anoxic episode requiring resuscitation within 6 months of the Screening Visit.
10. Subject has moderate or severe hepatic impairment. Asymptomatic subjects with mild hepatic impairment (elevated liver enzymes < 3x 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.
11. Subject has severe renal impairment (estimated glomerlular filtration rate <30mL/min/1.73m2)
12. Subject is receiving concomitant therapy with any of the following: 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; other centrally-acting noradrenergic agonists, including atomexetine; or cyproheptadine (see Appendix 1 for a complete list of prohibited medications). (Note: Short-term medication requirements for prohibted medications will be handled on a per case basis by the Medical Monitor.)
13. Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at the Screening Visit.
14. Subject is taking felbamate for less than 1 year prior to screening and/or does not have stable liver function and hematology laboratory tests, and/or the dose has not been stable for at least 60 days prior to the Screening Visit.
15. Subject is known to be human immunodeficiency virus (HIV) positive.
16. Subject is known to have active viral hepatitis (B or C)
17. Subject is currently receiving an investigational product.
18. Subject has participated in another clinical trial within the past 30 days (calculated from that study’s last scheduled visit). Participation in non-treatment trials will be reviewed by the medical monitor.
19. 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 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 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.
20. Subject is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
21. Subject is institutionalized in a general nursing home (ie, in a facility that does not provide skilled epilepsy care).
22. Subject does not have a reliable caregiver who can provide seizure diary information throughout the study.
23. Subject has a clinically significant condition, including chronic obstructive pulmonary disease, interstitial lung disease, or portal hypertension, 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) |
Part 1
Efficacy:
The efficacy endpoint for Part 1 of the study is:
• Number, frequency, and duration of countable seizures that result in drops for the 0.8 mg/kg/day
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Data from Part 1 will constitute the primary analyses of the study and will be performed upon database lock after the last subject enrolled has completed the last study visit of Part 1.
The frequency of seizures that result in drops during the Part 2 OLE Treatment Period will be compared to baseline frequency measured prior to randomization in Part 1. Both the mean and median change from baseline will be presented and the statistical significance of the change will be assessed using a Wilcoxon signed-rank test. Other secondary assessments will be compared to baseline from prior to Part 1, or by visit throughout Part 1 and Part 2, as appropriate. |
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| E.5.2 | Secondary end point(s) |
• Number, frequency, and duration of countable seizures that do not result in drops
• Number, frequency, and duration of all countable seizures by type
• Proportion of subjects who achieve a ≥25%, ≥50%, ≥75%, or 100% reduction from baseline in seizure frequency
• Number of seizure-free days
• Clinical Global Impression – Improvement as assessed by parent/caregiver
• Clinical Global Impression – Improvement as assessed by principal investigator
• Affective symptoms of parent/caregiver using the HADS scale
• Number of episodes of status epilepticus
• Number of instances of rescue medication use and number of doses
• Incidence in use of medical services to treat seizures
Efficacy endpoints for Part 2 are identical, with the exception of the HADS and CGI assessments, which are exploratory during the open-label extension.
Safety:
The safety endpoints for Part1 and Part 2 of the study are:
• AEs
• Laboratory safety (hematology, chemistry, urinalysis)
• Vital signs (blood pressure, heart rate, temperature, and respiratory rate)
• Physical examination
• Neurological examination
• BRIEF to measure changes in cognition of the subject
• Columbia Suicidality Severity Rating Scale (C-SSRS)
• 12-lead ECGs
• Doppler ECHOs
• Body weight and BMI
Exploratory:
The exploratory endpoints for Part 1 and Part 2 of the study are:
• VABS
• QOLCE
• Zarit Caregiver Burden Inventory
Pharmacokinetics:
Steady-state plasma fenfluramine and norfenfluramine PK parameters (average plasma concentration (Cavg ss) and area under the concentration time curve from time zero to time=t (AUC0-t) after administration of ZX008 derived using a PBPK model. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Denmark |
| Finland |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Japan |
| Mexico |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Switzerland |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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