Stopping TSC Onset and Progression 2: Epilepsy Prevention in TSC Infants (STOP2)

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).

Study Overview

• Status: Completed
• Conditions: Epilepsy; Tuberous Sclerosis Complex
• Intervention / Treatment: Drug: TAVT-18 (sirolimus)

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 Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 6 months (Child)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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. 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	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. Adaptive Scale: Minimum = 20, Maximum = 140, Standard deviation is +/- 15	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. 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	12 and 24 months of age

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Darcy Krueger, MD, PhD, Children's Hospital Medical Center, Cincinnati

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2020
• Primary Completion (Actual): December 15, 2022
• Study Completion (Actual): December 15, 2022

Study Registration Dates

• First Submitted: October 6, 2020
• First Submitted That Met QC Criteria: October 19, 2020
• First Posted (Actual): October 20, 2020

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: April 19, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Congenital Abnormalities; Genetic Diseases, Inborn; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Neurocutaneous Syndromes; Hamartoma; Neoplasms, Multiple Primary; Epilepsy; Tuberous Sclerosis; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 2019-1045

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No