| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of seizures in children and young adults with genetically confirmed cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Seizures due to cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) |
|
| 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 | 10032062 |
| E.1.2 | Term | Other forms of epilepsy, with intractable epilepsy |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 efficacy of ganaxolone compared with placebo as adjunctive therapy for the treatment of seizures in children and young adults with genetically confirmed CDD at the end of the 17-week double-blind phase. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess behavioral/neuropsychiatric changes correlated with domains of attention, sleep, and a target behavior chosen by the parent/caregiver, using objective tests of central nervous system (CNS) function for ganaxolone compared with placebo as adjunctive therapy at the end of the 17-week double-blind phase.
- To assess the safety and tolerability of ganaxolone compared with placebo as adjunctive therapy at the end of the 17-week double-blind phase.
- To assess pharmacokinetic (PK) parameters in subjects receiving ganaxolone doses up to 63 mg/kg/day (1800 mg/day maximum) throughout the study.
- To assess the long-term efficacy, safety, and tolerability of ganaxolone when administered as adjunctive therapy throughout the open-label phase. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. (a) Molecular confirmation of a pathogenic or likely pathogenic CDKL5 variant, early onset, difficult to control seizures, and neurodevelopmental impairment is required. The principal investigator (PI) must review the results of the genetic analysis and confirm that the causal relationship to the epilepsy syndrome is likely. If the subject has a de novo variant of unknown significance (VUS) in the kinase domain of the CDKL5, parental testing is negative and meets all other inclusion criteria, then the subject can be included.
But, if the mutation is outside the kinase domain and all other inclusion criteria are met or if there is any uncertainty of the pathogenicity of the CDKL5 mutation by the site PI, then the study inclusion should be reviewed and determined by the sponsor/sponsor delegate. Genetic mutations will be confirmed by the sponsor’s chosen central laboratory. Subjects must have (b) seizure onset by 1 year of age and
(c) lack of independent ambulation by 2 years of age.
2. Male or female subjects aged 2 through 21 years, inclusive.
3. Subject/parent or LAR willing to give written informed consent/assent, after being properly informed of the nature and risks of the study and prior to engaging in any study-related procedures.
4. Failure to control seizures despite appropriate trial of 2 or more anti-seizure mediations at therapeutic doses.
5. Have at least 16 seizures of primary seizure types: bilateral tonic (sustained motor activity ≥ 3 seconds), generalized tonic-clonic, bilateral clonic, atonic/drop or focal to bilateral tonic-clonic per 28 days in each 1-month period in the 2-month period prior to screening.
6. Subject must be approved to participate by sponsor and/or designee (i.e., Epilepsy Consortium) after review of medical history, genetic testing, seizure classification, and historical seizure calendars.
7. Participants should be on a stable regimen of 0-4 anti-seizure medications for ≥ 1 month prior to the screening visit, without a foreseeable change in dosing for the duration of the double-blind phase. Vagus nerve stimulator (VNS), ketogenic diet, and modified Atkins diet do not count towards this limit but must be unchanged for 3 months prior to screening.
8. Subjects with surgically implanted VNS will be allowed to enter the study provided that all of the following conditions are met:
a. The VNS has been in place for ≥ 1 year prior to the screening visit.
b. The settings must have remained constant for 3 months prior to the screening visit and remain constant throughout the double-blind phase.
c. The battery is expected to last for the duration of the double-blind phase.
9. Felbamate: The use of felbamate is allowed provided that the subject has been maintained on a stable dose of felbamate for > 6 months and has had stable liver function (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and hematology during the course of treatment, and is expected to remain constant throughout the double-blind phase.
10. Parent/caregiver is able and willing to maintain an accurate and complete daily electronic seizure calendar for the duration of the study.
11. Able and willing to take investigational product with food 3 times daily if dosed with oral suspension or 2 times daily if dosed with oral capsules. Ganaxolone must be administered with food.
12. Sexually active female of childbearing potential must be using a medically acceptable method of birth control and have a negative quantitative serum β-human chorionic growth hormone (β-HCG) test collected at the initial screening visit. Childbearing potential is defined as a female who is biologically capable of becoming pregnant. A medically acceptable method of birth control includes intrauterine devices in place for at least 3 months prior to screening, surgical sterilization, or adequate barrier methods (e.g., diaphragm and foam). An oral contraceptive alone is not considered adequate for the purpose of this study. Use of oral contraceptives in combination with another method (e.g., a spermicidal cream) is acceptable. In subjects who are not sexually active, abstinence is an acceptable form. |
|
| E.4 | Principal exclusion criteria |
1. Previous exposure to GNX.
2. Pregnant or breastfeeding.
3. West Syndrome with hypsarrhythmia pattern on EEG or seizures predominantly of Infantile Spasms (IS) type; if EEG pattern/seizure type is uncertain, study inclusion should be reviewed and determined by the sponsor/sponsor delegate.
4. Concurrent use of adrenocorticotropic hormone (ACTH), prednisone or other glucocorticoid is not permitted, nor use of moderate or strong inducers or inhibitors of CYP3A4/5/7. A list of CYP3A4/5/7 inhibitors and inducers is included in Section 12.1.
5. Subjects on ACTH, prednisone or other systemically (non-inhaled) administered steroids should be off the product greater than 28 days prior to screening. Concomitant PRN topical or intranasal steroids for dermatologic reactions and allergic rhinitis are allowed and do not warrant exclusion from the study.
6. Subjects with a positive result on tetrahydrocannabinol (THC) or cannabidiol (CBD) test (via urine or plasma drug screen) at the screening visit, and a positive result on THC or CBD test (via plasma) at the baseline visit will be excluded from the study. Tetrahydrocannabinol and/or CBD will be allowed in the open-label phase.
7. Use of dietary supplements or herbal preparations are not permitted if subject has been using them consistently for less than 3 months prior to screening, or does not plan on remaining on stable doses for the duration of the double-blind phase. Use of St. John’s Wort is not permitted (See Section 12.1).
8. Changes in any medications within the last month prior to screening. All concomitant medications must be stable in dose for at least 1-month prior to screening unless otherwise noted.
9. Have an active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive as evaluated by brain imaging (magnetic resonance imaging [MRI]).
10. Have any disease or condition (medical or surgical; other than CDKL5) at screening that might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the investigational product, or would place the subject at increased risk.
11. An AST (serum glutamic oxaloacetic transaminase [SGOT]) or ALT (serum glutamic pyruvic transaminase [SGPT]) greater than 3 times the upper limit of normal (ULN) at study entry. If AST or ALT increases > 3 times ULN during the study, subject should be followed with weekly laboratory repeat testing and continue in study if levels trending down. Subject will be discontinued if levels do not decline to under 3 x ULN.
12. Total bilirubin levels greater than ULN at study entry. In cases of documented, stable medical condition (i.e., Gilbert’s Syndrome) resulting in levels of total bilirubin greater than ULN, the medical monitor can determine if a protocol exception can be made. If total bilirubin increases to 1.5 x ULN or more during study, the subject will be discontinued.
13. Subjects with significant renal insufficiency, estimated glomerular filtration rate (eGFR) < 30 mL/min (calculated using the Cockcroft-Gault formula or Pediatric GFR calculator or Bedside Schwartz), will be excluded from study entry or will be discontinued if the criterion is met post baseline.
14. Have been exposed to any other investigational drug within 30 days or less than 5 half-lives prior to screening.
15. Unwillingness to withhold grapefruit, Seville oranges or star fruit from diet during the entire clinical trial.
16. Unwillingness to withhold alcohol throughout the entire clinical trial.
17. Have active suicidal plan/intent or have had active suicidal thoughts in the past 6 months or a suicide attempt in the past 3 years.
18. Known sensitivity or allergy to any component in the investigational product(s), progesterone or other related steroid compounds. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the percent change in 28-day seizure frequency through the end of the 17-week, double-blind treatment phase relative to the 6-week prospective baseline period. The primary seizure types include bilateral tonic (sustained motor activity ≥ 3 seconds), generalized tonic-clonic, bilateral clonic, atonic/drop seizures or focal to bilateral tonic-clonic. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 6-week prospective baseline period and end of the 17 week double blind treatment phase |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints (Seizure control): Derived seizure secondary efficacy endpoints will be based on data through the end of the 17-week double-blind treatment phase relative to the 6-week prospective baseline period.
- Arithmetic change in percentage of seizure-free days, based on primary seizure types
- Arithmetic change in longest seizure free interval, based on primary seizure types
- CGI-CSID: seizure intensity and duration
Secondary Efficacy Endpoints (Behavioral/Neuropsychiatric):
- CGICA
- CGI-C in parent/caregiver/LAR identified behavioral target - potential domains include sociability, communication, irritability, and hyperactivity
- CGI-I: overall improvement by both parent/caregiver/LAR and clinician |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 6-week prospective baseline period and end of the 17 week double blind treatment phase |
|
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open label - 17 weeks double blinded followed by up to 3 year open label |
|
| 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 | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Germany |
| Israel |
| Italy |
| 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 | |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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