STOP2: Stopping TSC Onset and Progression 2: Epilepsy Prevention in TSC Infants
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Stage 1 Open Label 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)
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.
|
Outcome Measures
Primary Outcome Measures
- 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
- 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)
- 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 type [12 and 24 months of age]
Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types
- 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.
- 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.
- 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.
Eligibility Criteria
Criteria
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)
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Has a confirmed diagnosis of TSC based on established clinical or genetic criteria
Exclusion Criteria:
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Prior history of seizures (clinical or electrographic) at the time of enrollment or identified on baseline EEG
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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
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Has taken any other investigational drug as part of another research study, within 30 days prior to the baseline screening visit
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Has a significant illness or active infection at the time of the baseline screening visit
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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)
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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
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Prior, planned or anticipated neurosurgery within 3 months of the baseline visit
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Has a TSC-associated condition for which mTOR treatment is clinically indicated (i.e. SEGA or AML)
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Subjects who are, in the opinion of the investigator, unable to comply with the requirements of the study
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cincinnati Children's Hospital | Cincinnati | Ohio | United States | 45229 |
Sponsors and Collaborators
- Children's Hospital Medical Center, Cincinnati
Investigators
- Principal Investigator: Darcy Krueger, MD, PhD, Children's Hospital Medical Center, Cincinnati
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2019-1045