NCT04595513: STOP2

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

Completed Phase 1, PHASE2 Results posted Last updated 16 May 2024

What this trial tests

Phase 1, PHASE2 trial testing TAVT-18 (sirolimus) in Tuberous Sclerosis Complex in 5 participants. Completed in 15 December 2022.

Timeline

8 September 2020

Primary endpoint
15 December 2022

15 December 2022

Quick facts

Lead sponsor	Children's Hospital Medical Center, Cincinnati
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	prevention
Enrollment	5
Start date	8 September 2020
Primary completion	15 December 2022
Estimated completion	15 December 2022
Sites	1 location across United States

Drugs / interventions tested

• TAVT-18 (sirolimus) — full drug profile →

Conditions studied

• Tuberous Sclerosis Complex — all drugs for Tuberous Sclerosis Complex →
• Epilepsy — all drugs for Epilepsy →

Sponsor

Children's Hospital Medical Center, Cincinnati

Who can join

Adults 1 Day to 6 Months, any sex, with Tuberous Sclerosis Complex or Epilepsy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Safety - Adverse Events Primary · 12 months of age

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

Group	Value	95% CI
Stage 1 Open Label	40

Efficacy - Time to Seizure Onset Primary · 12 months of age

Time from treatment initiation to seizure onset

Group	Value	95% CI
Stage 1 Open Label	102	26 – 178

Treatment Discontinuance Due to Adverse Events Secondary · 12 months of age

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

Group	Value	95% CI
Stage 1 Open Label	20

Treatment Disruption Due to Adverse Events Secondary · 12 months of age

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

Group	Value	95% CI
Stage 1 Open Label	19.5	0 – 54

Precision Dosing Accuracy Secondary · 12 months of age

Blood trough concentration of sirolimus (ng/ml)

Group	Value	95% CI
Stage 1 Open Label	6.6	3.6 – 9.3

Age at Seizure Onset Secondary · 12 and 24 months of age

Patient age in months at time of seizure onset

Group	Value	95% CI
Stage 1 Open Label	10.6	2.9 – 19.7

Seizure Type Secondary · 12 and 24 months of age

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

12 months of Age -- Infantile Spasms

Group	Value	95% CI
Stage 1 Open Label	40

12 months of Age -- Focal Seizures

Group	Value	95% CI
Stage 1 Open Label	20

24 months of Age -- Infantile Spasms

Group	Value	95% CI
Stage 1 Open Label	40

24 months of Age -- Focal Seizures

Group	Value	95% CI
Stage 1 Open Label	60

Seizure Frequency Secondary · 12 and 24 months of age

Number of seizures in past 30 days

12 months of Age

Group	Value	95% CI
Stage 1 Open Label	0

24 months of Age

Group	Value	95% CI
Stage 1 Open Label	0

TAND Severity Assessed by the TAND-L Checklist Secondary · 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. 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 months of Age -- Parent Rating

Group	Value	95% CI
Stage 1 Open Label	2	0 – 5

12 months of Age -- Clinician Rating

Group	Value	95% CI
Stage 1 Open Label	2	0 – 5

24 months of Age -- Parent Rating

Group	Value	95% CI
Stage 1 Open Label	1	0 – 2

24 months of Age -- Clinician Rating

Group	Value	95% CI
Stage 1 Open Label	3.5	0 – 4

Adaptive Behavior Assessed by the the VABS Secondary · 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. Adaptive Scale: Minimum = 20, Maximum = 140, Standard deviation is +/- 15

12 months of Age -- Adaptive Behavior Composite Score

Group	Value	95% CI
Stage 1 Open Label	91	86 – 102

24 months of age -- Adaptive Behavior Composite Score

Group	Value	95% CI
Stage 1 Open Label	88	68 – 128

Global Neurodevelopment Assessed by the Bayley Scales of Infant Development Secondary · 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. 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 months of Age -- Cognitive Domain

Group	Value	95% CI
Stage 1 Open Label	90	70 – 110

12 months of Age -- Language Domain

Group	Value	95% CI
Stage 1 Open Label	89	75 – 100

12 months of Age -- Motor Domain

Group	Value	95% CI
Stage 1 Open Label	87	72 – 112

24 months of Age -- Cognitive Domain

Group	Value	95% CI
Stage 1 Open Label	95	70 – 100

24 months of Age -- Language Domain

Group	Value	95% CI
Stage 1 Open Label	77	70 – 92

24 months of Age -- Motor Domain

Group	Value	95% CI
Stage 1 Open Label	74	74 – 87

Adverse events — posted to ClinicalTrials.gov

Time frame: 12 months of Age. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Stage 1 Open Label

Serious: 0/5 (0%)

Deaths: 0/5

Other adverse events (27 terms — click to expand)

Reaction	System	Stage 1 Open Label
Hypertriglyceridemia	Metabolism and nutrition disorders	—
Rhinitis	Infections and infestations	—
Otitis Media	Infections and infestations	—
Hypercholesterolemia	Metabolism and nutrition disorders	—
Tussis (cough)	Respiratory, thoracic and mediastinal disorders	—
Constipation	Gastrointestinal disorders	—
Excessive Flatulence	Gastrointestinal disorders	—
Stomatitis (mouth sores/ulcers)	Gastrointestinal disorders	—
Pyrexia (fever)	General disorders	—
Insomnia	Psychiatric disorders	—
Rhinorrhea (Congestion)	Respiratory, thoracic and mediastinal disorders	—
Emesis (vomiting)	Gastrointestinal disorders	—
Hematochezia (Bloody stool)	Gastrointestinal disorders	—
Diarrhea	Gastrointestinal disorders	—
Fussiness	General disorders	—
Discomfort/Pain due to Teething	General disorders	—
Fatigue	General disorders	—
Rash (Allergic reaction)	Immune system disorders	—
Rhinosinusitis (Sinus infection)	Infections and infestations	—
Abscess w/Infection	Infections and infestations	—
Croup w/Stridor	Infections and infestations	—
Respiratory Syncytial Virus (RSV)	Infections and infestations	—
Hand-Foot-Mouth Disease	Infections and infestations	—
Lip Lesion	Skin and subcutaneous tissue disorders	—
Dermatitis	Skin and subcutaneous tissue disorders	—
Eczema	Skin and subcutaneous tissue disorders	—
Hypertension	Vascular disorders	—

Data from ClinicalTrials.gov NCT04595513 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Current Approaches and Future Directions for the Treatment of mTORopathies.
   Karalis V, Bateup HS. · · 2021 · cited 62× · PMID 33910214 · DOI 10.1159/000515672
2. Perfect match: mTOR inhibitors and tuberous sclerosis complex.
   Luo C, Ye WR, Shi W, Yin P, et al · · 2022 · cited 52× · PMID 35246210 · DOI 10.1186/s13023-022-02266-0
3. Precision Therapy for Epilepsy Related to Brain Malformations.
   D'Gama AM, Poduri A. · · 2021 · cited 30× · PMID 34608615 · DOI 10.1007/s13311-021-01122-6
4. Epilepsy Characteristics in Neurodevelopmental Disorders: Research from Patient Cohorts and Animal Models Focusing on Autism Spectrum Disorder.
   Chakraborty S, Parayil R, Mishra S, Nongthomba U, et al · · 2022 · cited 18× · PMID 36142719 · DOI 10.3390/ijms231810807
5. FDA-Approved Kinase Inhibitors in Preclinical and Clinical Trials for Neurological Disorders.
   Lui A, Vanleuven J, Perekopskiy D, Liu D, et al · · 2022 · cited 15× · PMID 36558997 · DOI 10.3390/ph15121546
6. Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment.
   Vasic V, Jones MSO, Haslinger D, Knaus LS, et al · · 2021 · cited 14× · PMID 34828352 · DOI 10.3390/genes12111746
7. Preventative treatment of tuberous sclerosis complex with sirolimus: Phase I safety and efficacy results.
   Capal JK, Ritter DM, Franz DN, Griffith M, et al · · 2024 · cited 8× · PMID 39726432 · DOI 10.1002/cns3.20070
8. Treatment-Resistant Epilepsy and Tuberous Sclerosis Complex: Treatment, Maintenance, and Future Directions.
   Singh A, Hadjinicolaou A, Peters JM, Salussolia CL. · · 2023 · cited 8× · PMID 37041855 · DOI 10.2147/ndt.s347327