Stopping TSC Onset and Progression 2B: Sirolimus TSC Epilepsy Prevention Study

Study Overview
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Brief Summary
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This trial is a Phase II randomized, double-blind, placebo controlled multi-site study to evaluate the safety and efficacy of early sirolimus to prevent or delay seizure onset in TSC infants. This study is supported by research funding from the Office of Orphan Products Division (OOPD) of the US Food and Drug Administration (FDA).

Detailed Description
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Tuberous Sclerosis Complex (TSC) is caused by genetic mutation in TSC1 or TSC2, resulting in dysregulation of the mechanistic target of rapamycin (mTOR) signaling pathway. Age at time of seizure onset in TSC infants has been linked to long-term neurodevelopmental outcome in this high-risk population. Sirolimus is an mTOR inhibitor used to treat many of the symptoms of TSC, including epilepsy. This will be the first study to truly evaluate a targeted, disease-modifying drug therapy for preventing or delaying seizure onset in TSC using a rational, mechanism-based therapeutic approach.

Official Title
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Stopping TSC Onset and Progression 2B: Sirolimus TSC Epilepsy Prevention Study

Conditions
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Tuberous Sclerosis Complex, Epilepsy

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 0-6 months of age at the time of enrollment (subject must be <7 months of chronological age at time of randomization and treatment initiation). Corrected age must be at least 39 weeks (calculated by subtracting the number of weeks born before 40 weeks gestation from the chronological age). Has a confirmed diagnosis of TSC based on established clinical or genetic criteria Exclusion Criteria: Prior history of seizures (clinical or electrographic) at the time of enrollment or identified on baseline EEG. Has been treated in the past or is currently being treated at the time of enrollment with conventional anticonvulsant medications (AEDs), systemic (oral) mTOR inhibitors (such as rapamycin, sirolimus, or everolimus), ketogenic-related special diet, or another anti-seizure therapeutic agent, device, or procedure. Has taken any other investigational drug as part of another research study, within 30 days prior to the baseline screening visit. Has a significant illness or active infection at the time of the baseline screening visit Has a history of significant prematurity, defined as gestational age <30 weeks at the time of delivery, or other significant medical complications at birth or during the neonatal period that other than TSC would convey additional risk of seizures or neurodevelopmental delay (i.e. HIE, severe neonatal infection, major surgery, prolonged ventilatory or other life-saving supportive care or procedures). Abnormal laboratory values at baseline (i.e., renal function, liver function, or bone marrow production) that are in the opinion of the investigator clinically significant and may jeopardize the safety of the study subject. Prior, planned or anticipated neurosurgery within 3 months of the baseline visit Has a TSC-associated condition for which mTOR treatment is clinically indicated (i.e. SEGA or AML). Subjects who are, in the opinion of the investigator, unable to comply with the requirements of the study.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This trial will employ a randomized, double-blind, placebo-controlled multisite design to evaluate the safety and efficacy of early sirolimus treatment to prevent or delay seizure onset in TSC infants.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus<br>Sirolimus | Drug: Sirolimus<br>* The investigational drug product to be used in this study is sirolimus, provided in oral suspension.<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy -- time to seizure onset | Time to seizure onset, comparing sirolimus with placebo | 12 months of age | 
| Safety -- adverse events | Percentage of subjects reporting severe (CTCAE v5.0 grade >= 3) adverse event (AE) or serious adverse event (SAE), comparing sirolimus with placebo. | 12 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurodevelopmental Outcomes | Neurodevelopmental outcomes at the end of treatment, comparing sirolimus with placebo. | 12 and 24 months of age | 
| Quality of Life Outcomes | Patient and caregiver quality of life, comparing sirolimus with placebo. | 12 and 24 months of age | 
| EEG Biomarkers | EEG measures of neuronal connectivity, comparing sirolimus with placebo. | 12 and 24 months of age | 
| MRI Biomarkers | MRI measures of neuronal connectivity, comparing sirolimus with placebo. | 12 and 24 months of age | 
| Sirolimus Precision Dosing | Validate the feasibility and effectiveness of sirolimus precision dosing in infants with TSC | 12 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberous Sclerosis Complex, TSC, epilepsy, prevention, mTOR, sirolimus, infant