Epilepsy, Tuberous Sclerosis Complex
Conditions
Keywords
Tuberous Sclerosis Complex, TSC, epilepsy, prevention, mTOR, sirolimus, infant
Brief summary
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
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.
Interventions
DRUGSirolimus
The investigational drug product to be used in this study is sirolimus, provided in oral suspension.
DRUGPlacebo
Matching placebo
Sponsors
Darcy Krueger
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
1 Days to 6 Months
Healthy volunteers
No
Inclusion criteria
1. 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). 2. Has a confirmed diagnosis of TSC based on established clinical or genetic criteria
Exclusion criteria
1. Prior history of seizures (clinical or electrographic) at the time of enrollment or identified on baseline EEG. 2. 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. 3. Has taken any other investigational drug as part of another research study, within 30 days prior to the baseline screening visit. 4. Has a significant illness or active infection at the time of the baseline screening visit 5. 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). 6. 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. 7. Prior, planned or anticipated neurosurgery within 3 months of the baseline visit 8. Has a TSC-associated condition for which mTOR treatment is clinically indicated (i.e. SEGA or AML). 9. Subjects who are, in the opinion of the investigator, unable to comply with the requirements of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy -- time to seizure onset | 12 months of age | Time to seizure onset, comparing sirolimus with placebo |
| 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), comparing sirolimus with placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neurodevelopmental Outcomes | 12 and 24 months of age | Neurodevelopmental outcomes at the end of treatment, comparing sirolimus with placebo. |
| Quality of Life Outcomes | 12 and 24 months of age | Patient and caregiver quality of life, comparing sirolimus with placebo. |
| EEG Biomarkers | 12 and 24 months of age | EEG measures of neuronal connectivity, comparing sirolimus with placebo. |
| MRI Biomarkers | 12 and 24 months of age | MRI measures of neuronal connectivity, comparing sirolimus with placebo. |
| Sirolimus Precision Dosing | 12 months of age | Validate the feasibility and effectiveness of sirolimus precision dosing in infants with TSC |
Countries
United States
Contacts
CONTACTMolly S Griffith, BA
CONTACTJessica Krefting, RN
PRINCIPAL_INVESTIGATORDarcy A Krueger, MD, PhD
Children's Hospital Medical Center, Cincinnati
PRINCIPAL_INVESTIGATORMartina Bebin, MD, MPA
University of Alabama at Birmingham
Outcome results
None listed