TSC-STEPS: Stopping TSC Onset and Progression 2B: Sirolimus TSC Epilepsy Prevention Study

Sponsor

Darcy Krueger (Other)

Overall Status

Recruiting

CT.gov ID

NCT05104983

Collaborator

(none)

Enrollment

Locations

Arms

56.5

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Tuberous Sclerosis Complex Epilepsy	Drug: Sirolimus Drug: Placebo	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. 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

64 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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.

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Prevention

Official Title:

Stopping TSC Onset and Progression 2B: Sirolimus TSC Epilepsy Prevention Study

Actual Study Start Date :

Oct 13, 2021

Anticipated Primary Completion Date :

Jun 30, 2025

Anticipated Study Completion Date :

Jun 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sirolimus Sirolimus	Drug: Sirolimus The investigational drug product to be used in this study is sirolimus, provided in oral suspension.
Placebo Comparator: Placebo Placebo	Drug: Placebo Matching placebo

Arm

Intervention/Treatment

Experimental: Sirolimus

Sirolimus

Drug: Sirolimus

The investigational drug product to be used in this study is sirolimus, provided in oral suspension.

Placebo Comparator: Placebo

Placebo

Drug: Placebo

Matching placebo

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day to 6 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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).
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	University of California at Los Angeles	Los Angeles	California	United States	90095
3	Stanford University	Palo Alto	California	United States	94304
4	Boston Children's Hospital	Boston	Massachusetts	United States	02115
5	Washington University -- St. Louis	Saint Louis	Missouri	United States	63110
6	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27510
7	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
8	University of Texas HSC at Houston	Houston	Texas	United States	77030

Sponsors and Collaborators

Darcy Krueger

Investigators

Principal Investigator: Darcy A Krueger, MD, PhD, Children's Hospital Medical Center, Cincinnati
Principal Investigator: Martina Bebin, MD, MPA, University of Alabama at Birmingham