Adjunctive GNX Treatment Compared With Placebo in Children and Adults With TSC-related Epilepsy

This is a Phase 3, global, double-blind, randomized, placebo-controlled study of adjunctive GNX treatment in children and adults with TSC-related epilepsy. The study consists of a 4-week prospective Baseline phase, defined as the first 28 days following screening, followed by a double-blind phase consisting of a 4-week titration period (Day 1 to Day 28) and a 12-week maintenance period (Day 29 to Week 16).


Eligibility Criteria:
Inclusion Criteria:

1. Clinical or mutational diagnosis of TSC consistent with:

   1. Molecular confirmation of a pathogenic mutation in TSC1 or TSC2. A pathogenic mutation is defined as a mutation that clearly prevents protein synthesis and/or inactivates the function of the TSC1 or TSC2 proteins (eg, nonsense mutation or frameshift mutations, large genomic deletions) or is a missense mutation whose effect on protein function has been established by functional assessment. The Principal investigator (PI) or designee must review the results of the genetic analysis and confirm that the causal relationship to the epilepsy syndrome is likely. OR
   2. Clinical diagnosis of definite TSC which includes 2 major features or 1 major feature with ≥ 2 minor features.
2. Male or female participants aged 1 through 65 years, inclusive. For Europe (EU), Middle East and North Africa (MENA), and Oceania (OC) Male or Female participants aged 2 through 65 years, inclusive.
3. Participant/parent(s) or LAR(s) 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. If the participant is not qualified nor able to provide written informed consent based on age, developmental stage, intellectual capacity, or other factors, parent(s)/LAR(s) must provide consent for study participation, if appropriate.
4. Failure to control seizures despite appropriate trial of 2 or more Anti-seizure medication (ASMs) at therapeutic doses and for adequate duration of treatment per PI judgment.
5. Participants should be on a stable regimen of ASMs (including moderate or strong inducer or inhibitor ASM eg, carbamazepine, phenytoin, etc.) at therapeutic doses for ≥ 28 days prior to the screening visit, and without a foreseeable change in dosing for the duration of the study. (Note: Minor dose adjustment to address tolerability and safety events may be allowed on case-by-case basis and it should be discussed with the study medical monitor.)
6. A history of at least 8 countable seizures per month in the 2 months prior to screening with no more than 1 seizure free week in each month. This includes seizures of any kind.
7. Have at least 8 primary endpoint seizures in the first 28 days following the screening visit.

   The primary endpoint seizure types are defined as the following:
   1. focal motor seizures without impairment of consciousness or awareness
   2. focal seizures with impairment of consciousness or awareness with motor features
   3. focal seizures evolving to bilateral, tonic-clonic seizures
   4. generalized motor seizures including tonic-clonic, bilateral tonic, bilateral clonic, or atonic/drop seizures.

   Seizures that do not count towards the primary endpoint include:
   1. Focal or generalized nonmotor seizures (eg, absence seizures or focal nonmotor seizures with or without impairment of awareness)
   2. Infantile or epileptic spasms
   3. Myoclonic seizures.
8. Participants with surgically implanted vagal nerve stimulator (VNS) will be allowed to enter the study provided that all of the following conditions are met:

   1. The VNS has been in place for ≥ 6 months prior to the screening visit.
   2. The settings must have remained constant for 3 months prior to the screening visit and are expected to remain constant throughout the study.
   3. The battery is expected to last for the duration of the study.
9. Parent(s)/caregiver(s)/LAR(s) or the participant, as appropriate, is (are) willing and able to maintain an accurate and complete daily seizure eDiary for the duration of the study.
10. Willing and able to take IP (suspension) as directed with food (TID).
11. Women of childbearing potential (WOCBP) must be using a medically acceptable method of birth control and have a negative quantitative serum beta-human chorionic growth hormone (β-HCG) test collected at the initial screening and Baseline visits.Childbearing potential is defined as a female who is biologically capable of becoming pregnant. A medically acceptable method of birth control includes intrauterine devices (that have been in place for at least 1 month prior to the screening visit), hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and implants), and surgical sterilization (such as oophorectomy or tubal ligation. When used consistently and correctly, "double-barrier" methods of contraception can be used as an effective alternative to highly effective contraception methods. Contraceptive measures such as Plan B™, sold for emergency use after unprotected sex, are not acceptable methods for routine use.
12. Male participants must agree to use highly effective contraceptive methods during the study and for 30 days after the last dose of IP. Highly effective methods of contraception include surgical sterilization (such as a vasectomy) and adequate "double-barrier" methods.

Exclusion Criteria:

1. Previous exposure to GNX.
2. Pregnant or breastfeeding.
3. Participants who have been taking felbamate for less than 1 year prior to screening.
4. Participants taking cannabidiol (CBD) preparations other than Epidiolex.
5. A positive result on plasma drug screen for CBD or tetrahydrocannabinol (THC) at Visit 1 (screening), with the exception of results that are fully explained by Epidiolex, which can be adjusted by the investigator in the event of any Adverse events (AEs).
6. Concurrent use of adrenocorticotropic hormone (ACTH), prednisone or other glucocorticoid is not permitted, nor use of the strong inducers of cytochrome P450 3A4 (CYP3A4), rifampin and St John's Wort. Participants on ACTH, prednisone, or other systemically (non-inhaled or topical) administered steroids should be off the product \> 28 days prior to screening. Rifampin and St John's Wort must be discontinued at least 28 days before Visit 2, study drug initiation.

   Note:
   1. Use of concomitant intranasal or pro re nata (PRN) topical steroids for dermatologic reactions and allergic rhinitis are allowed during the study.
   2. This exclusion criterion does not prohibit the use of approved ASMs.
7. Changes in any chronic medications within the 4 weeks prior to the screening visit. All chronic concomitant medications must be relatively stable in dose for at least 4 weeks prior to the screening visit unless otherwise noted. Small dose adjustment to manage tolerability and safety events is permitted and should be discussed with the study medical monitor.
8. Participants who have epilepsy surgery planned during the study or who have undergone surgery for epilepsy within the 6 months prior to screening.
9. An active central nervous system (CNS) infection, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive as evaluated by brain magnetic resonance imaging (MRI). This includes tumor growth which in the opinion of the investigator could affect primary endpoint seizure control.
10. Any disease or condition (medical or surgical; other than TSC) at the screening visit that might compromise the hematologic, cardiovascular (including any cardiac conduction defect), pulmonary, renal, gastrointestinal, or hepatic systems; or other conditions that might interfere with the absorption, distribution, metabolism, or excretion of the IP, or would place the participant at increased risk or interfere with the assessment of safety/efficacy. This may include any illness in the past 4 weeks which in the opinion of the investigator may affect seizure frequency.
11. Hepatic impairment sufficient to affect participant safety, or an aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT) \> 3 × the upper limit of normal (ULN) at screening or Baseline visits and confirmed by a repeat test.
12. Biliary impairment sufficient to affect participant safety, or total bilirubin levels \> 1.5 × ULN at screening or Baseline visit and confirmed by a repeat test. In cases of Gilbert's Syndrome, resulting in stable levels of total bilirubin greater than ULN, the medical monitor can determine if a protocol exception can be made
13. Renal impairment sufficient to affect participant safety, or estimated glomerular filtration rate (eGFR) \< 30 milliliter per minute (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. Cases of temporary renal insufficiency should be discussed with the medical monitor to determine the participant's study continuation.
14. Exposed to any other investigational drug or investigational device within 30 days or fewer than 5 half-lives prior to the screening visit. For therapies in which half-life cannot be readily established, the Sponsor's Medical Monitor should be consulted.
15. Unwillingness to avoid excessive alcohol use throughout the study.
16. Have active suicidal plan/intent, active suicidal thoughts or a suicide attempt in the past 6 months.
17. Known sensitivity or allergy to any component in the IP(s), progesterone, or other related steroid compounds.
18. Participants deprived of their liberty by a judicial or administrative decision, or for psychiatric treatment, or participants admitted to a health or social services facility for purposes other than research.
19. Participants receiving traditional Chinese medicine therapies within the prior 28 days of the screening.