Efficacy and Safety Evaluation of Basimglurant as Adjunctive Therapy in Tuberous Sclerosis Complex-Associated Seizures in Pediatric and Young Adult Populations

The primary objective of this study is to evaluate the **efficacy** of daily administration of basimglurant, adjunctive to ongoing anticonvulsive therapy, compared with placebo in patients with **Tuberous Sclerosis Complex** (TSC). This is clinically relevant as it aims to determine the potential of basimglurant to enhance seizure control in this patient population, which could lead to improved management of TSC-associated seizures.

Secondary objectives include:

• Evaluating the impact of treatment on functioning at school and during social activities.
• Determining the effect of basimglurant on the severity of symptoms of TSC.
• Determining the longest seizure-free interval (i.e., seizure-free days).
• Evaluating the number of patients considered treatment responders.
• Evaluating the safety of basimglurant in children, adolescents, and young adults with seizures associated with TSC.
• Investigating the proportion of patients tolerating each dose during dose escalation.
• Investigating the long-term safety of basimglurant in children, adolescents, and young adults with seizures associated with TSC.

The clinical trial involves a total of **36 participants** diagnosed with **Tuberous Sclerosis Complex** (TSC). The study population includes both male and female subjects, aged between **5 to 30 years**. Participants were selected based on their documented history of TSC and refractory seizure history, and they are currently receiving one or more anti-epileptic drugs (AEDs). The trial population is characterized by a stable medication regimen for epilepsy for at least 30 days prior to study entry. Participants are required to have the ability and willingness to provide informed assent or consent, and they must be fluent in the language of the study staff. The study also includes vulnerable populations, and female participants of childbearing potential must agree to undergo pregnancy testing and use contraception during the trial period. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is a **Phase 2B**, multicenter, 30-week, prospective, cross-over, double-blind, randomized, placebo-controlled study, followed by a 52-week open-label extension. The primary objective is to evaluate the efficacy and safety of **basimglurant** as an adjunctive treatment to ongoing anticonvulsive therapy in children, adolescents, and young adults with seizures associated with **Tuberous Sclerosis Complex**. The trial is designed to compare the effects of daily basimglurant administration with a placebo, both adjunctive to existing anticonvulsive treatments.

The trial will commence with a screening visit to assess eligibility based on inclusion criteria such as age, documented history of Tuberous Sclerosis Complex, and current anticonvulsive therapy. Participants will be randomized to receive either basimglurant or placebo in a double-blind manner. The study will include multiple follow-up visits to monitor efficacy and safety, with primary endpoints focusing on monthly seizure counts during the 12-week treatment periods. Secondary endpoints will assess changes in the Sheehan Disability Scale score, Caregiver Global Impression of Change, and seizure-free days, among others.

The overall duration of the trial is estimated to be 82 weeks, with participant involvement expected to last approximately 30 weeks for the double-blind phase, followed by an optional 52-week open-label extension. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is expected to conclude by August 2025, with recruitment starting in August 2024.

The clinical trial involves the administration of **Basimglurant**, a chemical compound with the active substance name **BASIMGLURANT**. It is provided in the form of a capsule, with a pharmaceutical form display as "CAPSULE". The capsules are intended for **oral use**. The maximum daily dose of Basimglurant is 3.5 mg, with a total maximum dose of 1487.5 mg over a treatment period of up to 72 weeks. The product is identified by the sponsor product code NOE-101 and is manufactured by NOEMA PHARMA AG. The chemical structure of Basimglurant is also known as 2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridinium sulphate. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes a **placebo** treatment, which is designed to match the Basimglurant capsules in appearance. The placebo consists of microcrystalline cellulose spheres (Vivapur 1000) encapsulated in a hard gelatin capsule with an opaque white body and cap, size 1. The placebo is administered orally, following the same dosing schedule as the active treatment, to maintain the double-blind nature of the trial. The placebo serves as a comparator to evaluate the efficacy and safety of Basimglurant when used adjunctively with ongoing anticonvulsive therapy in patients with Tuberous Sclerosis Complex.

The efficacy of Basimglurant as an adjunctive treatment for seizures associated with **Tuberous Sclerosis Complex** will be assessed through a series of primary and secondary endpoints. The primary endpoint involves the evaluation of monthly seizure counts of countable seizure types over a 28-day period during the 12-week treatment phases, specifically in Period 2 and Period 4. Secondary endpoints include changes from baseline in the Sheehan Disability Scale (SDS) score at Week 16 in Period 2 and at Week 30 in Period 4, as well as the Caregiver Global Impression of Change (CGIC) score at the same time points. Additionally, the study will measure monthly seizure-free days, and assess seizure response rates defined by reductions of 25%, 50%, and 75% from baseline in monthly seizure counts during the 12-week treatment periods.

Data collection will occur at specified intervals, with efficacy parameters being measured at baseline and at designated weeks throughout the study. The study will utilize validated scales such as the Sheehan Disability Scale and the Caregiver Global Impression of Change to quantify changes in patient condition. The analysis will focus on comparing the efficacy of Basimglurant against placebo when used alongside ongoing anticonvulsive therapy. The study is structured as a double-blind, randomized, placebo-controlled trial, followed by an open-label extension, to ensure robust and reliable efficacy data.