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

Primary Purpose

Tuberous Sclerosis Complex, Epilepsy

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

TAVT-18 (sirolimus)

About this trial

This is an interventional prevention trial for Tuberous Sclerosis Complex

Eligibility Criteria

1 Day - 6 Months (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Cincinnati Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Stage 1 Open Label

Arm Description

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.

Outcomes

Primary Outcome Measures

Safety - adverse events

Percentage of subjects reporting severe (CTCAE v5.0 grade >= 3) adverse event (AE) or serious adverse event (SAE)

Efficacy - time to seizure onset

Time from treatment initiation to seizure onset

Secondary Outcome Measures

Treatment discontinuance due to adverse events

Percentage of subjects that reduce or discontinue treatment due to an AE or SAE (any grade)

Treatment disruption due to adverse events

Number of days treatment is withheld due to an AE or SAE (any grade).

Precision dosing accuracy

Blood trough concentration of sirolimus (ng/ml)

Age at seizure onset

Patient age in months at time of seizure onset

Seizure type

Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types

Seizure frequency

Number of seizures in past 30 days

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.

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.

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.

Full Information

NCT ID

NCT04595513

First Posted

October 6, 2020

Last Updated

March 21, 2023

Sponsor

Children's Hospital Medical Center, Cincinnati

1. Study Identification

Unique Protocol Identification Number

NCT04595513

Brief Title

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

Acronym

STOP2

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Completed

Study Start Date

September 8, 2020 (Actual)

Primary Completion Date

December 15, 2022 (Actual)

Study Completion Date

December 15, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Children's Hospital Medical Center, Cincinnati

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberous Sclerosis Complex, Epilepsy

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

This trial is a single stage, phase I/II clinical trial design. Treatment is open-label to verify safety and dosing for TAVT-18 in TSC infants. Note that this clinical trial originally planned for a follow-up second stage employing a randomized, double-blind, placebo-controlled multisite design. In October 2021, the second stage of this study was replaced by the TSC-STEPS clinical trial (clinicaltrials.gov NCT05104983).

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Stage 1 Open Label

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

TAVT-18 (sirolimus)

Intervention Description

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.

Primary Outcome Measure Information:

Title

Safety - adverse events

Description

Percentage of subjects reporting severe (CTCAE v5.0 grade >= 3) adverse event (AE) or serious adverse event (SAE)

Time Frame

12 months of age

Title

Efficacy - time to seizure onset

Description

Time from treatment initiation to seizure onset

Time Frame

12 months of age

Secondary Outcome Measure Information:

Title

Treatment discontinuance due to adverse events

Description

Percentage of subjects that reduce or discontinue treatment due to an AE or SAE (any grade)

Time Frame

12 months of age

Title

Treatment disruption due to adverse events

Description

Number of days treatment is withheld due to an AE or SAE (any grade).

Time Frame

12 months of age

Title

Precision dosing accuracy

Description

Blood trough concentration of sirolimus (ng/ml)

Time Frame

12 months of age

Title

Age at seizure onset

Description

Patient age in months at time of seizure onset

Time Frame

12 and 24 months of age

Title

Seizure type

Description

Percentage of subjects reporting infantile spasms, focal seizures, or other seizure types

Time Frame

12 and 24 months of age

Title

Seizure frequency

Description

Number of seizures in past 30 days

Time Frame

12 and 24 months of age

Title

TAND severity assessed by the TAND-L Checklist

Description

Time Frame

12 and 24 months of age

Title

Adaptive behavior assessed by the the VABS

Description

Time Frame

12 and 24 months of age

Title

Global neurodevelopment assessed by the Bayley Scales of Infant Development

Description

Time Frame

12 and 24 months of age

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Day

Maximum Age & Unit of Time

6 Months

Accepts Healthy Volunteers

Eligibility 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) 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Darcy Krueger, MD, PhD

Organizational Affiliation

Children's Hospital Medical Center, Cincinnati

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cincinnati Children's Hospital

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

12. IPD Sharing Statement

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

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