Phase 3 Open-label Study of Adjunctive Ganaxolone in Tuberous Sclerosis Complex-Related Epilepsy in Pediatric and Adult Populations

The primary objective of this study is to assess the long-term **safety** and tolerability of Ganaxolone (GNX) as an adjunctive therapy for seizures associated with Tuberous Sclerosis Complex (TSC) in both children and adults. This is clinically relevant as it aims to provide a comprehensive understanding of the potential risks and benefits of long-term GNX use in managing TSC-related epilepsy, which is crucial for optimizing patient care and treatment strategies.

Secondary objectives include:

• Determining the percentage of change from baseline in 28-day seizure frequency during open-label treatment for the first year.
• Assessing the change in frequency of countable focal seizures from baseline during open-label treatment for the first year.
• Evaluating changes in mood, behavior, and quality of life using the SF-36 for the first year.
• Assessing overall clinical outcome using CGI-I scores by the clinician and the parent(s)/caregiver(s)/LAR(s).
• Evaluating changes in seizure intensity and duration using the CGI-CSID.

The clinical trial involves a total of **115 participants** diagnosed with **Tuberous Sclerosis Complex (TSC) related epilepsy**. The study population includes both male and female subjects, encompassing a broad **age range** from children to adults. Participants were selected based on their completion of prior studies, specifically Study 1042-TSC-3001 or ongoing eligibility in Study 1042-TSC-2001. The trial includes a vulnerable population, indicating that special considerations are in place for the protection and ethical treatment of participants. Lifestyle considerations include the requirement for participants to take the investigational product with food three times a day. Additionally, participants or their caregivers must maintain a daily seizure diary. The trial ensures that women of childbearing potential use medically acceptable methods of birth control, while male participants agree to use highly effective contraceptive methods during and after the study period. The primary objective is to assess the long-term safety and tolerability of GNX as an adjunctive therapy for seizures associated with TSC.

The clinical trial is a **Phase 3, open-label study** designed to evaluate the long-term safety and tolerability of **ganaxolone** as an adjunctive therapy for seizures associated with **Tuberous Sclerosis Complex (TSC)-related epilepsy** in both children and adults. The trial will enroll approximately 169 participants who have previously completed Study 1042-TSC-3001 or continue to meet the requirements of Study 1042-TSC-2001. Participants will receive **ganaxolone** in capsule form, administered orally three times a day with food. The study is structured to include a 52-week treatment and maintenance period, followed by a 2-week taper period, and a subsequent 2-week safety follow-up period.

The trial will commence with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria, which include the completion of prior studies and the ability to provide informed consent. Participants will be required to maintain a daily seizure diary throughout the study. The primary endpoints focus on the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and any dose reductions due to AEs. Secondary endpoints include the percentage change from baseline in 28-day seizure frequency and the number of participants considered treatment responders during the first year.

Study visits will be scheduled at regular intervals to monitor participants' health and response to treatment. These visits will include assessments such as vital sign measurements, physical and neurological examinations, 12-lead ECGs, and clinical laboratory tests. The end-of-study visit will occur after the safety follow-up period to ensure comprehensive evaluation of the treatment's effects. The expected duration of participant involvement is approximately 56 weeks, including the taper and follow-up periods. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or withdrawal of consent by the participant or their legal representative.

The clinical trial involves the administration of **Ganaxolone**, an experimental medication, in the form of a **capsule**. Ganaxolone is a chemical entity classified as a neurosteroid. It is provided by Marinus Pharmaceuticals Inc. The active substance in the medication is ganaxolone, which is chemically derived. The pharmaceutical form of the medication is a capsule, intended for **oral use**. The maximum daily dose of Ganaxolone is 1800 mg, with a total maximum dose of 1922400 mg over the course of the treatment period. The maximum treatment period is 36 months. The medication is not formulated specifically for pediatric use, although it is being tested in both children and adults. Ganaxolone has been designated as an orphan drug, indicating its use in the treatment of a rare condition.

In this study, Ganaxolone is used as an adjunctive therapy for seizures associated with **Tuberous Sclerosis Complex (TSC)**-related epilepsy. The trial is open-label, meaning that both the researchers and participants are aware of the treatment being administered. The primary objective of the trial is to assess the long-term safety and tolerability of Ganaxolone when used in conjunction with other standard-of-care therapies for TSC-related epilepsy. No placebo or comparator treatment is used in this study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence and severity of adverse events (AEs), serious adverse events (SAEs), withdrawals, and dose reductions due to AEs. Additionally, vital sign measurements such as blood pressure, heart rate, respiratory rate, body temperature, height, and body weight will be monitored. Physical, neurological, and developmental examinations, 12-lead ECGs, clinical laboratory tests, and the Columbia-Suicide Severity Rating Scale (C-SSRS) will also be utilized to evaluate efficacy.

Secondary endpoints focus on the percentage change from baseline in 28-day seizure frequency during both the open-label and long-term treatment phases, specifically during the first year. The number and percentage of participants considered treatment responders will be recorded, along with the Clinical Global Impression-Improvement (CGI-I) at the last scheduled study visit. Changes from baseline in the quality-of-life scale SF-36 and the percentage of seizure-free days during treatment, based on seizure type, will be assessed. Additionally, changes from baseline of the Clinical Global Impression-Change in Seizure Intensity and Duration (CGI-CSID) will be measured.