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

A Phase 3, Double-blind, Randomized, Placebo-controlled Trial of Adjunctive Ganaxolone (GNX) Treatment in Children and Adults With Tuberous Sclerosis Complex (TSC)-Related Epilepsy (TrustTSC)

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).

Study Overview

• Status: Completed
• Conditions: Tuberous Sclerosis Complex
• Intervention / Treatment: Drug: Placebo; Drug: Ganaxolone

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Heidelberg, Australia, 3084
    • Austin Health
  • Melbourne, Australia, 3004
    • Alfred Health
  • Parkville, Australia, 3050
    • Royal Melbourne Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
• Canada
  • Montreal, Canada, H2X 0C2
    • Hôtel Dieu de Montréal - CHUM
  • Montréal, Canada, H3T 1C5
    • CHU Sainte-Justine
  • Toronto, Canada, M5G 1X8
    • The Hospital for Sick Children
  • Toronto, Canada, M5T 2S8
    • Toronto Western Hospital
  • Vancouver, Canada, V6H 3V4
    • BC Children's Hospital
• China
  • Beijing, China, 100034
    • Peking University First Hospital
  • Beijing, China, 100080
    • Chinese PLA General Hospital
  • Chengdu, China, 610000
    • Chengdu's Women and Children's Central Hospital
  • Jilin
    • Chang chun, Jilin, China, 130028
      • First Hospital of Jilin University
  • Nanchang City
    • Jiangxi, Nanchang City, China, 330000
      • Jiangxi Provincial Children's Hospital
  • Xicheng District
    • Beijing, Xicheng District, China, 100045
      • Beijing Children Hospital, Capital Medical University
  • Yunyan District
    • Guiyang, Yunyan District, China, 550004
      • The Affiliated Hospital of Guizhou Medical University
• France
  • Bron, France, 69229
    • University Hospital of Lyon
  • Rennes, France, 35033
    • University Hospital of Rennes
  • Strasbourg, France, 67084
    • University of Strasbourg
• Germany
  • Bielefeld, Germany, 33617
    • Epilepsie-Zentrum Bethel - Krankenhaus Mara
  • Bonn, Germany, 53127
    • University Hospital Bonn
  • Frankfurt, Germany, 60528
    • ZNN - Epilepsiezentrum Frankfurt am Main
  • Freiburg, Germany, 79106
    • Universitäts Krankenhaus Freiburg
  • Herdecke, Germany, 58313
    • Gemeinschaftskrankenhaus Herdecke
  • Radeberg, Germany, 01454
    • Epilepsiezentrum Kleinwachau gGmbH
• Israel
  • Petah Tikva, Israel, 4920235
    • Schneider Children´s Medical Center
  • Tel Hashomer, Israel, 52621
    • Sheba Medical Center
• Italy
  • Bari, Italy, 1170124
    • Department of Neurology and Sense Organs, AOU Policlinico di Bari
  • Genova, Italy, 16147
    • Pediatric Neurology and Muscular Diseases Unit - University of Genoa
  • Rome, Italy, 00185
    • Policlinico Umberto I
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Nino Jesus
  • Madrid, Spain, 28034
    • Hospital Ruber International
  • Málaga, Spain, 29010
    • Hospital Regional Universitario de Málaga
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La Fe
• United Kingdom
  • Bristol, United Kingdom, BS2 8AE
    • Bristol Royal Hospital for Children
  • Oxford, United Kingdom, OX3 9DU
    • NHS acute tertiary referral centre, John Radcliffe Hospital
  • Salford, United Kingdom, M6 8HD
    • Salford Royal Hospital
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Children's Hospital
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Research Institute
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Mattel Children's Hospital, TSC Center
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Diego, California, United States, 92123
      • University of California, San Diego
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Childrens Hospital Colorado
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours Children's Hospital - Delaware Valley
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida Gainesville
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Health
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Mid-Atlantic Epilepsy and Sleep Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Rochester
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hosptial
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Charlotte, North Carolina, United States, 28207
      • Atrium Health/Levine Children's Hospital
    • Durham, North Carolina, United States, 27712
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Children's Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • Le Bonheur Children's Hospital
  • Texas
    • Austin, Texas, United States, 78757
      • Child Neurology Consultants of Austin (CNCA)
    • Dallas, Texas, United States, 75207
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • McGovern Medical School at the University of Texas Health Science Center
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Health Care-Pediatric Neurology
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo matching GNX; oral suspension, TID	Drug: Placebo; Placebo will be administered
Experimental: Ganaxolone (GNX); oral suspension, 3 times a day (TID)	Drug: Ganaxolone; GNX will be administered

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in 28-day Seizure Frequency for Primary Seizure Type During Double Blind Period	Primary seizures include atonic/drop, bilateral clonic, bilateral tonic, focal motor with altered awareness, focal motor with intact awareness, focal to bilateral tonic-clonic seizures, focal with hypotonia impaired awareness, and generalized tonic-clonic. Seizure frequency was calculated as the total number of seizures divided by the number of days with seizure data in the period, multiplied by 28. Percent change from Baseline in 28-day seizure frequency was calculated as follows for each participant: post-baseline 28-day seizure frequency minus baseline 28-day seizure frequency whole divided by baseline 28-day seizure frequency and multiplied by 100.	Baseline (Day 1), Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Were Considered as Treatment Responders During Double Blind Period	Treatment responders are defined as those participants with ≥ 50% reduction from Baseline in primary seizure type frequency during the given period.	Up to 16 weeks
Number of Responders to Clinical Global Impression of Improvement (CGI-I) Scale as Assessed by Parent/Caregiver	The CGI-I is a 7-point Likert scale that the parent(s)/caregiver(s)/ legally authorized representative (LAR) and clinician uses to rate the change in overall seizure control, behavior, safety, and tolerability after initiation of the IP relative to baseline (prior to treatment with the IP). The participant was rated as follows: 1 - very much improved, 2 - much improved, 3 - minimally improved, 4 - no change, 5 - minimally worse, 6 - much worse, and 7 - very much worse. Higher scores indicated worse condition. Number of responders to each score on the scale has been presented.	Baseline (Day 1) through 16 weeks
Number of Responders to Clinical Global Impression of Improvement (CGI-I) Scale as Assessed by Clinician	The CGI-I is a 7-point Likert scale that the parent(s)/caregiver(s)/ LAR and clinician uses to rate the change in overall seizure control, behavior, safety, and tolerability after initiation of the IP relative to baseline (prior to treatment with the IP). The participant was rated as follows: 1 - very much improved, 2 - much improved, 3 - minimally improved, 4 - no change, 5 - minimally worse, 6 - much worse, and 7 - very much worse. Number of responders to each score on the scale has been presented.	Baseline (Day 1) through 16 weeks

Collaborators and Investigators

• Sponsor: Marinus Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Actual): September 9, 2024
• Study Completion (Actual): October 14, 2024

Study Registration Dates

• First Submitted: March 21, 2022
• First Submitted That Met QC Criteria: April 7, 2022
• First Posted (Actual): April 12, 2022

Study Record Updates

• Last Update Posted (Actual): July 11, 2025
• Last Update Submitted That Met QC Criteria: June 24, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Adjunctive; Ganaxolone; Tuberous Sclerosis Complex-Related Epilepsy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neoplasms; Genetic Diseases, Inborn; Neurodegenerative Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Sclerosis; Tuberous Sclerosis; Epilepsy; Neurosteroids; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; GABA Modulators; GABA Agents; Ganaxolone
• Other Study ID Numbers: 1042-TSC-3001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No