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

Phase 1

Completed

Conditions: Tuberous Sclerosis Complex
Epilepsy

Interventions: Drug: TAVT-18 (sirolimus)

Registration Number: NCT04595513

Lead Sponsor: Children's Hospital Medical Center, Cincinnati

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 5

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Stage 1 Open Label	TAVT-18 (sirolimus)	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.

Primary Outcome Measures

Name	Time	Method
Safety - Adverse Events	12 months of age	Percentage of subjects reporting severe (CTCAE v5.0 grade \>= 3) adverse event (AE) or serious adverse event (SAE)
Efficacy - Time to Seizure Onset	12 months of age	Time from treatment initiation to seizure onset

Secondary Outcome Measures

Name	Time	Method
Treatment Discontinuance Due to Adverse Events	12 months of age	Percentage of subjects that reduce or discontinue treatment due to an AE or SAE (any grade)
Seizure Type	12 and 24 months of age	Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types
Treatment Disruption Due to Adverse Events	12 months of age	Number of days treatment is withheld due to an AE or SAE (any grade).
Precision Dosing Accuracy	12 months of age	Blood trough concentration of sirolimus (ng/ml)
Age at Seizure Onset	12 and 24 months of age	Patient age in months at time of seizure onset
Seizure Frequency	12 and 24 months of age	Number of seizures in past 30 days
TAND Severity Assessed by the TAND-L Checklist	12 and 24 months of age	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. Parent Rating: "Considering all of the issues reported today how much have these bothered, troubled, or distressed you/your child/family?"; Min = 0 Max = 10; higher values indicate greater concern. Clinician Rating: "Interviewer's judgement of impact/burden on the individual/child/family."; Min = 0 Max = 10; higher values indicate greater concern
Adaptive Behavior Assessed by the the VABS	12 and 24 months of age	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. Adaptive Scale: Minimum = 20, Maximum = 140, Standard deviation is +/- 15
Global Neurodevelopment Assessed by the Bayley Scales of Infant Development	12 and 24 months of age	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. Cognitive Domain: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15 Language Domain: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15 Motor Doman: Minimum = 40, Maximum = 160, Standard Deviation is +/- 15