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 (with 2 additional weeks allowed, if necessary, for tolerance) and a 12-week maintenance period.
- Clinical or mutational diagnosis of TSC consistent with (Northrup and Krueger, 2013):
- 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 PI or designee must review the results of the genetic analysis and confirm that the causal relationship to the epilepsy syndrome is likely. OR
- Clinical diagnosis of definite TSC which includes 2 major features or 1 major feature with ≥ 2 minor features.
- Male or female participants aged 1 through 65 years, inclusive.
- Participant/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.
- Assent for participants over 7 years of age should be obtained if appropriate.
- Failure to control seizures despite appropriate trial of 2 or more AEDs at therapeutic doses and for adequate duration of treatment per PI judgment.
- Participants should be on a stable regimen of AEDs (including moderate or strong inducer or inhibitor anti-seizure medications 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.)
- 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.
- Have an average of at least 2 primary endpoint seizures per week in the 28 days
following the screening visit.
The primary endpoint seizure types are defined as the following:
- focal motor seizures without impairment of consciousness or awareness
- focal seizures with impairment of consciousness or awareness with motor features
- focal seizures evolving to bilateral, tonic-clonic seizures
- generalized motor seizures including tonic-clonic, bilateral tonic, bilateral clonic, or atonic/drop seizures. Seizures that do not count towards the primary endpoint include:
- Focal aware seizures without motor features
- Focal and generalized nonmotor seizures (eg, absence or focal nonmotor seizures with or without impairment of awareness)
- Infantile or epileptic spasms
- Myoclonic seizures.
- Participants with surgically implanted VNS will be allowed to enter the study provided
that all of the following conditions are met:
- The VNS has been in place for ≥ 1 year prior to the screening visit.
- The settings must have remained constant for 3 months prior to the screening visit and are expected to remain constant throughout the study.
- The battery is expected to last for the duration of the study.
- Parent/caregiver or the participant, as appropriate, is able and willing to maintain an accurate and complete daily seizure eDiary for the duration of the study.
- Able and willing to take IP (suspension) as directed with food TID.
- Sexually active WOCBP must be using a medically acceptable method of birth control and have a negative quantitative serum 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 1 month prior to the screening visit, surgical sterilization, or adequate double barrier methods (eg, diaphragm or condom 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 (eg, a spermicidal cream) is acceptable. In participants who are not sexually active, abstinence is an acceptable method of birth control.
- Male participants must agree to take all necessary measures to avoid causing pregnancy in their sexual partners during the study and for 30 days after the last dose of IP. Medically acceptable contraceptives include surgical sterilization (such as a vasectomy) and a condom used with a spermicidal gel or foam.
- Previous exposure to GNX.
- Pregnant or breastfeeding.
- Participants who have been taking felbamate for less than 1 year prior to screening.
- Participants taking CBD preparations other than Epidiolex.
- A positive result on plasma drug screen for CBD or THC at Visit 1 (screening), with the exception of results that are fully explained by Epidiolex, which is being prescribed and managed by the investigator.
- Concurrent use of ACTH, prednisone or other glucocorticoid is not permitted, nor use
of the strong inducers of 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.
- Use of concomitant intranasal or PRN topical steroids for dermatologic reactions and allergic rhinitis are allowed during the study.
- This exclusion criterion does not prohibit the use of approved AEDs
- 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.
- Participants who have epilepsy surgery planned during the study or who have undergone surgery for epilepsy within the 6 months prior to screening.
- An active CNS infection, demyelinating disease, degenerative neurological disease, or CNS disease deemed progressive as evaluated by brain imaging (MRI). This includes tumor growth which in the opinion of the investigator could affect primary endpoint seizure control.
- 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.
- An AST/SGOT or ALT/SGPT > 3 × the ULN at screening or baseline visits and confirmed by a repeat test.
- Biliary impairment sufficient to affect patient 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
- Renal impairment sufficient to affect patient safety, or 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 (Levey et al, 2006). Cases of temporary renal insufficiency should be discussed with the medical monitor to determine the participant's study continuation
- 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.
- Unwillingness to avoid excessive alcohol use throughout the study.
- Have active suicidal plan/intent, active suicidal thoughts or a suicide attempt in the past 6 months.
- Known sensitivity or allergy to any component in the IP(s), progesterone, or other related steroid compounds.