Sirolimus for Tuberous Sclerosis

(TSC-STEPS Trial)

Recruiting in Palo Alto (17 mi)

+10 other locations

Overseen by E. Martina Bebin, MD, MPA

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Darcy Krueger

Must not be taking: Anticonvulsants, mTOR inhibitors

Disqualifiers: Seizures, Prematurity, Significant illness, others

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing sirolimus, a medication that helps control symptoms of Tuberous Sclerosis Complex (TSC), in infants. The goal is to prevent or delay seizures, which can impact long-term brain development. Sirolimus works by turning down the activity of a center in the body that doesn't function properly in TSC. Sirolimus has been studied for its potential to control seizures in pediatric patients with TSC and has shown promising results in improving seizure control.

Will I have to stop taking my current medications?

The trial requires that participants have not been treated with conventional anticonvulsant medications, mTOR inhibitors, or other anti-seizure treatments at the time of enrollment. If you are currently on these medications, you may not be eligible to participate.

What data supports the effectiveness of the drug Sirolimus for treating tuberous sclerosis?

Research shows that drugs similar to Sirolimus, like Everolimus, have been effective in treating symptoms of tuberous sclerosis complex, such as epilepsy and certain types of tumors. This suggests that Sirolimus might also be effective for these conditions. ^{1 2 3 4 5}

Is sirolimus safe for humans?

Sirolimus, also known as rapamycin, is generally well tolerated in humans, with side effects that are usually mild and manageable. Common side effects include mouth sores, high cholesterol, and some infections, but these are not severe for most people. ^{3 5 6 7 8}

How is the drug Sirolimus unique for treating Tuberous Sclerosis?

Sirolimus is unique for treating Tuberous Sclerosis because it targets the mTOR pathway, which is involved in cell growth control, and is being explored for its potential to treat various manifestations of the condition. Unlike other treatments, it can be used topically for skin lesions or orally, offering flexibility in administration. ^{7 9 10 11 12}

Research Team

Darcy Krueger, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

E. Martina Bebin, MD, MPA

Principal Investigator

University of Alabama at Birmingham

Eligibility Criteria

This trial is for infants diagnosed with Tuberous Sclerosis Complex (TSC), aged between 0-6 months. They must not have started any seizure medications, special diets, or other treatments related to TSC and should be generally healthy without significant prematurity (born after at least 30 weeks of gestation).

Inclusion Criteria

I have been diagnosed with TSC through clinical tests or genetic analysis.

My baby is between 0-6 months old and corrected age is at least 39 weeks.

Exclusion Criteria

I have been treated with seizure medications, special diets, or mTOR inhibitors.

I was born significantly premature or had complications at birth risking seizures or developmental delays.

I have had, or will have, brain surgery within 3 months of starting the trial.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sirolimus or placebo to evaluate the prevention or delay of seizure onset in TSC infants

12 months

Regular visits for monitoring and dosing adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neurodevelopmental and quality of life assessments

12 months

Follow-up visits at 12 and 24 months of age

Treatment Details

Interventions

• Placebo (Drug)
• Sirolimus (mTOR inhibitor)

Trial Overview The study tests the safety and effectiveness of Sirolimus in preventing or delaying seizures in infants with TSC. It's a Phase II trial where participants are randomly given either Sirolimus or a placebo without knowing which one they receive.

Participant Groups

Group I: Sirolimus Experimental Treatment 1 Intervention

Sirolimus

Group II: Placebo Placebo Group 1 Intervention

Placebo

Who Is Running the Clinical Trial?

Darcy Krueger

Lead Sponsor

Trials

1

Recruited

60+

Findings from Research

In a compassionate use trial involving 15 patients with tuberous sclerosis complex and therapy-resistant epilepsy, long-term treatment with Everolimus (EVO) resulted in significant seizure frequency reduction or increased seizure-free days for 80% of participants, with 40% becoming completely seizure-free.

Despite all patients experiencing at least one adverse effect, 92.5% reported only mild to moderate side effects, indicating that EVO is a safe and well-tolerated option for managing epilepsy in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term treatment with everolimus in TSC-associated therapy-resistant epilepsies. Wiegand, G., May, TW., Lehmann, I., et al.[2021]

A study involving 45 infants and young children under two years old with tuberous sclerosis complex (TSC) found that everolimus was the most commonly used mTOR inhibitor, primarily to treat refractory epilepsy, with treatment starting around 11.6 months of age.

While 78% of patients experienced at least one adverse event (AE), most were mild or moderate, and only 20% had severe AEs, indicating that mTOR inhibitors can be used safely in this population with careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience. Krueger, DA., Capal, JK., Curatolo, P., et al.[2021]

In a study of 64 patients with tuberous sclerosis complex (TSC), everolimus demonstrated effectiveness in reducing seizure frequency, with 31% of patients experiencing a significant reduction, particularly in those under 18 years of age.

Everolimus also effectively reduced or stabilized renal angiomyolipoma (rAML) size in 38% of patients and significantly decreased subependymal giant cell astrocytoma (SEGA) volume in three patients, although adverse effects were common, with 95% of patients reporting side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. Cockerell, I., Christensen, J., Hoei-Hansen, CE., et al.[2023]

In a study involving 23 children with tuberous sclerosis complex and intractable epilepsy, sirolimus treatment led to a 41% reduction in seizure frequency, although this result was not statistically significant (p = 0.11).

Among the 14 children who achieved the target sirolimus levels, there was a more pronounced 61% decrease in seizure frequency (p = 0.06), suggesting potential efficacy in those who respond well to the treatment, but overall, the study could not confirm a significant benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial. Overwater, IE., Rietman, AB., Bindels-de Heus, K., et al.[2021]

Oral everolimus significantly increased the likelihood of achieving a 50% reduction in the size of renal angiomyolipoma and subependymal giant cell astrocytoma in patients with tuberous sclerosis complex, based on a systematic review of three studies involving 263 participants.

While participants receiving treatment had a similar risk of adverse events compared to those on placebo, the treatment did lead to a higher risk of dose reductions or treatment interruptions, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin and rapalogs for tuberous sclerosis complex. Sasongko, TH., Ismail, NF., Zabidi-Hussin, Z.[2023]

In a study of 1576 individuals with tuberous sclerosis complex (TSC), 4% of those treated with mTOR inhibitors (everolimus or sirolimus) developed diabetes mellitus, compared to only 0.6% of those not treated, indicating a significant association between mTORi use and diabetes risk.

While mTOR inhibitors are generally well tolerated and effective for managing TSC symptoms, clinicians should monitor for potential diabetes development in patients receiving these medications, highlighting the need for early detection and further research into this risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetes in Individuals With Tuberous Sclerosis Complex Treated With mTOR Inhibitors. Agricola, K., Stires, G., Krueger, DA., et al.[2022]

The TOSCA study, involving 179 patients across 39 sites in 11 EU countries, found that everolimus has a manageable long-term safety profile for treating tuberous sclerosis complex (TSC), with no new safety signals identified during the study.

Common adverse events included stomatitis and hypercholesterolemia, but only 5.6% of patients discontinued treatment due to adverse effects, indicating that everolimus is generally well-tolerated in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Evidence Study on the Long-Term Safety of Everolimus in Patients With Tuberous Sclerosis Complex: Final Analysis Results. Ruiz-Falcó Rojas, ML., Feucht, M., Macaya, A., et al.[2022]

Oral everolimus significantly reduces the size of SEGA and renal angiomyolipoma by 50%, decreases seizure frequency by 25% to 50%, and shows beneficial effects on skin lesions, with no difference in total adverse events compared to placebo, although more participants required dose adjustments or experienced serious adverse events.

Topical rapamycin improves responses to skin lesions and facial angiofibroma, increases patient satisfaction, and carries a higher risk of any adverse events compared to placebo, but does not increase the risk of severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapamycin and rapalogs for tuberous sclerosis complex. Sasongko, TH., Kademane, K., Chai Soon Hou, S., et al.[2023]

In a long-term study involving 94 patients with tuberous sclerosis complex (TSC), the sirolimus gel demonstrated a high efficacy with response rates of 78.2% for angiofibromas, 66.7% for cephalic plaques, and 72.2% for hypomelanotic macules after over 52 weeks of treatment.

The sirolimus gel was well tolerated, with a low discontinuation rate due to adverse events (2.1%), and while some patients experienced mild side effects like application site irritation and dry skin, none were serious and most resolved quickly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial. Wataya-Kaneda, M., Nagai, H., Ohno, Y., et al.[2021]

Topical rapamycin (sirolimus) has shown significant and temporary efficacy in reducing the size and visibility of facial angiofibromas in patients with Tuberous Sclerosis Complex (TSC), with about 80% of patients in a study at Angers University Hospital experiencing impressive and sustained responses.

Long-term use of topical rapamycin is necessary to maintain skin improvements, and while the treatment is generally well-tolerated, there are ongoing concerns about the cost and accessibility of effective formulations for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of mTOR inhibitors (rapalogs) for the treatment of skin changes in tuberous sclerosis complex. Farges, D., Sigg, N., Ville, D., et al.[2023]

Sirolimus is a drug that inhibits mTOR, a key protein involved in cell growth, making it a promising candidate for cancer therapy, with ongoing phase II and III clinical studies in various cancers.

The drug is also being explored for treating tuberous sclerosis, a genetic disorder caused by mutations in TSC proteins, with current studies in animal models highlighting its potential effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular activity of sirolimus and its possible application in tuberous sclerosis treatment. Jozwiak, J., Jozwiak, S., Oldak, M.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Long-term treatment with everolimus in TSC-associated therapy-resistant epilepsies. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): Multicentre clinical experience. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Rapamycin and rapalogs for tuberous sclerosis complex. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Diabetes in Individuals With Tuberous Sclerosis Complex Treated With mTOR Inhibitors. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Successful topical rapamycin treatment for facial angiofibromata in two children. [2015]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Evidence Study on the Long-Term Safety of Everolimus in Patients With Tuberous Sclerosis Complex: Final Analysis Results. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Rapamycin and rapalogs for tuberous sclerosis complex. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial. [2021]

11. France pubmed.ncbi.nlm.nih.gov

Use of mTOR inhibitors (rapalogs) for the treatment of skin changes in tuberous sclerosis complex. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Molecular activity of sirolimus and its possible application in tuberous sclerosis treatment. [2021]