| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CDKL5 DEFICIENCY DISORDER |
|
| E.1.1.1 | Medical condition in easily understood language |
| CDKL5 deficiency disorder is characterized by seizures that begin in infancy, followed by significant delays in many aspects of development |
|
| 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 | 22.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10083005 |
| E.1.2 | Term | CDKL5 deficiency disorder |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1 Objectives:
Efficacy
• To demonstrate that ZX008 0.8 mg/kg/day is superior to placebo as an adjunctive therapy for pediatric and adult subjects with CDD
• To assess global improvement with ZX008 treatment in pediatric and adult subjects with CDD
Safety
• To characterize the safety and tolerability of ZX008 in pediatric and adult subjects with CDD
Pharmacokinetics
• To assess the pharmacokinetics (PK) of ZX008 at steady-state in pediatric and adult subjects with CDD
Part 2 Objectives:
Efficacy
• To assess long-term effectiveness of ZX008 as an adjunctive therapy for pediatric and adult subjects with CDD
• To assess global improvement with ZX008 treatment in pediatric and adult subjects with CDD
Safety
• To characterize the long-term safety and tolerability of ZX008 in pediatric and adult subjects with CDD |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject has a confirmed pathogenic or likely pathogenic mutation in the CDKL5 gene and a clinical diagnosis of CDD with epilepsy onset in the first year of life, plus motor and
developmental delays.
2. Subject is male or female, aged 1 to 35 years, inclusive, as of the day of the Screening Visit. Subjects aged 1 to < 2 years will ONLY be permitted to enroll in the trial AFTER the DSMB
has determined that it is appropriate to do so based on a planned unblinded interim safety review to be conducted after approximately 40 subjects aged ≥ 2 to 35 years have completed Visit 6.
3. Subject must have failed to achieve seizure control despite previous or current use of 2 or more AETs.
4. Subject is currently receiving at least 1 concomitant antiseizure treatment: antiseizure medication (ASM), vagus nerve stimulation (VNS), responsive neurostimulation (RNS), or ketogenic diet (KD). During the trial, rescue medications or interventions for rescue treatment of seizures will not be counted towards the total number of antiseizure treatments established at Baseline.
5. All medications or interventions for epilepsy (including VNS, RNS, and KD) must be stable prior to screening and are expected to remain stable throughout the study. In order to establish stability at BL, duration of treatment with medications or interventions for epilepsy prior to the
Screening visit must be as follows: VNS and RNS: ≥ 6 months duration; ASMs or KD: ≥ 4 weeks duration.
6. At the Screening Visit, parent/caregiver reports that subject has ≥ 4 countable motor seizures (CMS) per week. CMS include distinct seizures of the generalized tonic-clonic [GTC], bilateral clonic, bilateral tonic, atonic (drop), bilateral tonic/atonic (drop), or focal to bilateral tonic-clonic type lasting approximately 3 seconds or longer, to distinguish from short-clustered seizures, spasms, or jerks.
7. Subject (and/or subject’s parent[s]/legal guardian[s]) has provided written informed consent (and assent if applicable).
8. Subject (and/or subject’s parent/caregiver) is willing and able to comply with study requirements (including 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 drug.
2. Subject has a diagnosis of pulmonary arterial hypertension.
3. Subject has a clinically significant medical condition, including chronic obstructive pulmonary disease, interstitial lung disease, or portal hypertension, or has had clinically relevant symptoms or a clinically significant illness currently or 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.
4. Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke, severe ventricular arrhythmias, or clinically significant structural cardiac abnormality, including but not limited to mitral valve prolapse, atrial or ventricular septal defects, patent ductus arteriosus, and patent foramen ovale with reversal of shunt. (Note: Patent foramen ovale or a bicuspid aortic valve are not considered exclusionary.)
5. Subject has current eating disorder that suggests anorexia nervosa or bulimia.
6. Subject has a current or past history of glaucoma.
7. Subject is taking > 4 concomitant ASMs. Rescue medications are not included in the count.
8. Subject is receiving concomitant treatment with cannabidiol (CBD) other than Epidiolex/Epidyolex or is being actively treated with tetrahydrocannabinol (THC) or any
marijuana product for any condition. Disallowed medications are subject to wash-out requirements.
9. Subject has moderate to severe hepatic impairment, assessed based on the Child-Pugh system.
10. Subject has moderate to severe renal impairment (estimated glomerular filtration rate < 50 mL/min/1.73 m2 calculated with the Isotope Dilution Mass Spectrometry [IDMS] Traceable Schwartz equation for children and the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation for adults, using actual body weight).
11. 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 atomoxetine; or cyproheptadine. (Note: Short-term
requirements for prohibited medications will be handled on a per case basis by the Medical Monitor.)
12. Subject is currently receiving another investigational product(s) or has received another investigational product within 30 days or within <5 times the half-lives of the investigational product, whichever is longer, prior to the Screening Visit.
13. Female subjects of childbearing potential must not be pregnant or breastfeeding. Female subjects of childbearing potential must have a negative urine or serum pregnancy test at Screening. Subjects of childbearing or child-fathering potential must be willing to use an approved method of highly effective contraception, which includes abstinence, while participating in this study and for 90 days after the last dose of study drug.
14. Subject is known to be human immunodeficiency virus positive.
15. Subject is known to have active viral hepatitis B or C.
16. Subject is institutionalized in a facility that does not provide skilled epilepsy care.
17. Subject has previously been treated with Fintepla® (fenfluramine) prior to the Screening Visit. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of Part 1 is the primary endpoint of the entire study:
• Percentage change from Baseline in CMSF during Titration and Maintenance Periods (T+M) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| One time point at end of 14 weeks (T + M) period. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary:
• Achievement of a ≥ 50% reduction from Baseline in CMSF during T+M
• Achievement of a CGI-I rating of much or very much improved as assessed by the Investigator at the end of T+M
• Percentage change from Baseline in monthly CTG seizure frequency during T+M |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| One time point at end of 14 weeks (T + M) period. |
|
| 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 | No |
| 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 | 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| Georgia |
| Israel |
| Japan |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Portugal |
| Spain |
|
| 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
|
| After subject has received study drug for 1 year in the Part 2 OLE Treatment Period |
|
| 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 | 10 |
| 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 | 10 |
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