Stopping TSC Onset and Progression 2: Epilepsy Prevention in TSC Infants

Study Overview
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Brief Summary
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This phase I/II clinical trial is an open-label clinical trial design to verify safety and dosing for TAVT-18 (sirolimus) powder for oral solution in TSC infants (N=5).

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. TAVT-18 is a novel formulation of sirolimus, an mTOR inhibitor. This study evaluates TAVT-18 as 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 2: Epilepsy Prevention in TSC Infants

Conditions
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Tuberous Sclerosis Complex, Epilepsy

Intervention / Treatment
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* Drug: TAVT-18 (sirolimus)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 0-6 months of age at the time of enrollment (randomization and treatment initiation must occur before 7 months of age and infants born prematurely must have a corrected age of at least 39 weeks, calculated by subtracting the number of weeks born before 40 weeks gestation from the actual chronological age, in weeks) 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
Intervention Model: Single Group Assignment
Interventional Model Description: This trial is a single stage, phase I/II clinical trial design. Treatment is open-label to verify safety and dosing for TAVT-18 in TSC infants. Note that this clinical trial originally planned for a follow-up second stage employing a randomized, double-blind, placebo-controlled multisite design. In October 2021, the second stage of this study was replaced by the TSC-STEPS clinical trial (clinicaltrials.gov NCT05104983).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 Open Label<br>Phase I/II, open-label PK and initial safety analysis. TAVT-18 administered orally twice/daily to achieve precision dosing target of 10 ng/ml. Whole blood sirolimus levels are assessed at defined intervals on days 1, 7, and 14. After day 14, participants can elect to continue open-label treatment with TAVT-18 until 12 months of age. Final developmental outcomes are assessed at 24 months of age. | Drug: TAVT-18 (sirolimus)<br>* The investigational drug product to be used in this study is TAVT-18, a proprietary formulation of sirolimus in clinical development, by Tavanta Therapeutics, Inc. It is provided in a powder formulation in pre-measured vials.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment discontinuance due to adverse events | Percentage of subjects that reduce or discontinue treatment due to an AE or SAE (any grade) | 12 months of age | 
| Treatment disruption due to adverse events | Number of days treatment is withheld due to an AE or SAE (any grade). | 12 months of age | 
| Precision dosing accuracy | Blood trough concentration of sirolimus (ng/ml) | 12 months of age | 
| Age at seizure onset | Patient age in months at time of seizure onset | 12 and 24 months of age | 
| Seizure type | Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types | 12 and 24 months of age | 
| Seizure frequency | Number of seizures in past 30 days | 12 and 24 months of age | 
| TAND severity assessed by the TAND-L Checklist | Overall severity rating on the TSC-associated Neuropsychiatric Disorders-Lifetime Version (TAND-L) Checklist. The TAND-L Checklist severity rating ranges from 0-10, with higher values indicating greater concern. | 12 and 24 months of age | 
| Adaptive behavior assessed by the the VABS | Composite score on the Vineland Adaptive Behavior Scales (VABS). The VABS composite score is normed to 100 = average or 50% percentile in normal populations, with lower values indicative of greater concern. | 12 and 24 months of age | 
| Global neurodevelopment assessed by the Bayley Scales of Infant Development | Composite score on the Bayley Scales of Infant Development. The Bayley Scales of Infant Development is normed to 100 = average or 50% percentile in normal populations, with lower values indicative of greater concern. | 12 and 24 months of age |