Efficacy and Safety of Sirolimus in Drug-Resistant Epilepsy Associated with Tuberous Sclerosis Complex: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this multicenter, randomized, double-blind, placebo-controlled study is to evaluate the **safety**, tolerability, and efficacy of **rapamycin** in patients with drug-resistant epilepsy associated with **tuberous sclerosis complex** (TSC). This is clinically relevant as TSC is a genetic disorder that often leads to epilepsy, which can be resistant to conventional treatments, thus necessitating alternative therapeutic options.

Secondary objectives include assessing the impact of rapamycin on TSC-associated neuropsychiatric disorders (TAND) and TSC-associated tumors, including lesions in the brain, kidneys, retina, and skin, compared to placebo. These secondary outcomes are important for understanding the broader therapeutic potential of rapamycin in managing various manifestations of TSC beyond epilepsy.

The clinical trial involves participants diagnosed with **tuberous sclerosis complex** (TSC), specifically focusing on those with drug-resistant epilepsy and organ tumors associated with TSC. The study population includes both male and female subjects, ranging in age from 3 months to 55 years, with a body weight of at least 6 kg and a proper nutritional status as assessed by the investigator. Participants are required to have a definite diagnosis of TSC according to the Consensus criteria and must have experienced at least 8 seizures during a 4-week period. The trial population was selected based on these criteria, and it includes a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of **sirolimus** in patients with drug-resistant epilepsy associated with **tuberous sclerosis complex**. The trial is structured as a Phase III study, with an estimated duration from March 2022 to June 2027. Participants will be randomly assigned to receive either the active treatment, Rapamune 1 mg/mL oral solution, or a placebo, with the primary objective being to assess the safety, tolerability, and efficacy of sirolimus compared to placebo.

The trial will commence with an inclusion (screening) visit, where eligibility criteria will be assessed, including a confirmed diagnosis of tuberous sclerosis complex and drug-resistant epilepsy, among other criteria. Participants will then enter a double-blind core phase, during which they will receive the assigned treatment for a period of up to 12 weeks. The primary endpoints include the comparison of the number of patients achieving at least a 50% reduction in seizures per week and the number of adverse events between the sirolimus and placebo groups. Secondary endpoints will evaluate the number of seizures per week, days free of seizures, and the severity of adverse events.

Study visits will be scheduled at regular intervals throughout the trial to monitor participants' health, adherence to the treatment regimen, and any adverse events. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted. The expected length of participant involvement is approximately 12 weeks, with conditions for early termination including significant adverse events or non-compliance with study protocols. The trial aims to provide valuable insights into the potential benefits of sirolimus for individuals with drug-resistant epilepsy associated with tuberous sclerosis complex.

The clinical trial involves the administration of **Rapamune 1 mg/mL oral solution**, which contains the active substance **sirolimus**. This experimental medication is provided in the form of an **oral solution** and is intended for **oral use**. The maximum daily dose is set at 40 mg, with a total dose not exceeding 0.7 mg/kg. The treatment period is capped at 364 days. The solution is prepared under validated aseptic conditions and transferred to pharmacy bottles. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental treatment, the study includes a **placebo** control, which is represented by **Linseed oil**. This substance does not have a specified pharmaceutical form or active substance and is used to maintain the double-blind nature of the trial. The placebo is administered in a manner consistent with the experimental treatment to ensure blinding is maintained. The use of a placebo allows for the assessment of the efficacy and safety of the experimental medication, **Rapamune**, in comparison to a non-active treatment.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the comparison of the number of patients experiencing at least a 50% reduction in seizures per week during the last month of the core blinded phase compared to the screening phase, in the **rapamycin** versus placebo group. Additionally, the number of adverse events, classified according to the Common Terminology Criteria for Adverse Events (CTCAE), will be evaluated in both the rapamycin and placebo groups during the double-blind core phase.

Secondary endpoints will focus on the comparison of the number of seizures per week and the number of days free of seizures in the rapamycin versus placebo group over a 12-week treatment period in the double-blind core phase. The severity of adverse events, as per CTCAE classification, and the number of patients withdrawn from the study due to adverse events will also be assessed. These efficacy parameters will be measured and collected at specified timepoints throughout the trial to ensure comprehensive analysis and evaluation of the treatment's impact on drug-resistant epilepsy associated with tuberous sclerosis complex.