Long-Term Safety of Everolimus for Tuberous Sclerosis

Not currently recruiting at 108 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: Everolimus

Must not be taking: Experimental treatments

Disqualifiers: Discontinued everolimus, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: Up to 10 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the long-term safety of everolimus for individuals with tuberous sclerosis, a genetic disorder causing non-cancerous tumors, who also experience difficult-to-treat seizures. It targets those already benefiting from everolimus in a previous study. The trial aims to confirm the safety and effectiveness of continued medication use. Individuals still experiencing positive results with everolimus and meeting the study's criteria may qualify for participation. As a Phase 3 trial, this study represents the final step before FDA approval, allowing participants to contribute to the potential availability of a new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does allow the use of anti-epileptic drugs (AEDs) for seizure control. You should discuss your specific medications with the trial team to get a clear answer.

Is there any evidence suggesting that everolimus is likely to be safe for humans?

Research shows that everolimus is generally safe for people with tuberous sclerosis complex (TSC) over the long term. Studies have found no new safety issues with extended use of this medication. In one study, patients who took everolimus for about 34 months experienced few safety problems beyond those typical for short-term use. This suggests that the treatment is well-tolerated over time. Prospective trial participants may find these findings reassuring regarding its safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for TSC?

Unlike the standard treatments for tuberous sclerosis, which often include anticonvulsants and surgery to manage symptoms, everolimus acts on a different pathway. Everolimus is an mTOR inhibitor, which means it specifically targets and blocks the mTOR pathway that's overactive in tuberous sclerosis, helping to reduce the growth of tumors. Researchers are excited about everolimus because its action directly addresses the underlying cause of the condition rather than just treating symptoms, potentially offering a more effective long-term solution. Additionally, the availability of dispersible tablets makes it easier to administer, especially for patients who have difficulty swallowing pills.

What is the effectiveness track record for everolimus in treating tuberous sclerosis?

Research has shown that everolimus, the treatment under study in this trial, effectively treats tuberous sclerosis complex (TSC). Studies have found that everolimus reduces seizures in about 80% of people with TSC. It also shrinks or stabilizes certain types of tumors, such as rAML and SEGA, which can develop in TSC patients. By reducing tumor size, everolimus may lower the risk of related health issues. These findings support using everolimus as an effective treatment for managing TSC symptoms. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for patients with Tuberous Sclerosis Complex (TSC) and hard-to-treat seizures who are already part of the EXIST-3 study, taking everolimus, and seeing benefits. They must have followed the previous study's rules well and agree to keep doing so. People can't join if they've stopped everolimus in EXIST-3 or if it's now approved and paid for in their country.

Inclusion Criteria

Patient is willing and able to comply with scheduled visits and treatment plans

You are already taking everolimus as part of another study sponsored by Novartis, called EXIST-3, and have completed all the necessary steps for that study.

Patient has demonstrated compliance, as assessed by the Investigator, with the parent study protocol requirements

Exclusion Criteria

I am taking everolimus with other treatments for seizures, but AEDs are okay.

Patient has been permanently discontinued from everolimus study treatment in EXIST-3 study

Everolimus is approved and covered for my TSC-related seizures in my country.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants continue receiving everolimus treatment for long-term safety evaluation

Up to 10 years

Quarterly visits (every 12 weeks ± 2 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus

Trial Overview The trial is looking at the long-term safety of a drug called everolimus in patients with TSC who experience seizures that don’t respond well to other treatments. These patients have seen improvements from this drug during a prior study (EXIST-3) and will continue treatment under observation.

How Is the Trial Designed?

Group I: everolimus Experimental Treatment 1 Intervention

everolimus, 2mg dispersible tablets

Everolimus is already approved in United States, European Union for the following indications:

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

In a phase 3 study involving 366 patients with tuberous sclerosis complex and treatment-resistant seizures, everolimus significantly reduced seizure frequency compared to placebo, with response rates of 28.2% for low-exposure and 40.0% for high-exposure everolimus.

The safety profile of everolimus was acceptable, with serious adverse events occurring in 14% of patients in both the low and high exposure groups, indicating that while there are risks, the benefits in seizure reduction were notable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. French, JA., Lawson, JA., Yapici, Z., et al.[2022]

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]

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]

In a study of 15 children and adolescents with drug-resistant TSC-associated epilepsy, Everolimus demonstrated significant efficacy, with 80% of patients responding to treatment and 58% achieving seizure freedom after a median follow-up of 22 months.

Despite transient side effects in 93% of patients, Everolimus was well-tolerated, indicating it could be a promising treatment option for TSC-related epilepsies when monitored by experienced healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of Everolimus in children with TSC - associated epilepsy - Pilot data from an open single-center prospective study. Samueli, S., Abraham, K., Dressler, A., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38042867/

Effectiveness and safety of everolimus treatment in patients ... In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% ...

2. ojrd.biomedcentral.com ojrd.biomedcentral.com/articles/10.1186/s13023-023-02982-1

Effectiveness and safety of everolimus treatment in patients ... The results indicate that everolimus treatment reduces or stabilises rAML lesions, reduces risk of renal events, and reduces SEGA volume and ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1043661823002402

Paradigm shift in the treatment of tuberous sclerosis Moreover, a subsequent prospective open study from a single centre enrolling 15 patients, demonstrated the efficacy of everolimus in reducing seizures in 80% of ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10693167/

Effectiveness and safety of everolimus treatment in patients ... The results indicate that everolimus treatment reduces or stabilises rAML lesions, reduces risk of renal events, and reduces SEGA volume and risk of ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01713946

NCT01713946 | A Placebo-controlled Study of Efficacy & ... This study evaluated the efficacy and safety of two trough-ranges of everolimus given as adjunctive therapy in patients with tuberous sclerosis complex (TSC)

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3589289/

Everolimus long-term safety and efficacy in subependymal ... Everolimus therapy is safe and effective for longer term (median exposure 34.2 months) treatment of patients with TSC with SEGA.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35462939/

Real-World Evidence Study on the Long-Term Safety of ... The results demonstrate that everolimus has a manageable long-term safety profile in the TSC treatment setting. No new safety signals emerged.

8. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.802334/full

Real-World Evidence Study on the Long-Term Safety of ... The results demonstrate that everolimus has a manageable long-term safety profile in the TSC treatment setting. No new safety signals emerged.

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0887899414006559

Long-Term Everolimus Treatment in Individuals With ... From the limited data available, long-term administration of everolimus appears feasible with few safety concerns beyond those associated with short-term use.