Rapamycin + Everolimus for Aging

(RESTOR Trial)

Overseen By Dean L Kellogg, Jr, MD PhD

Age: 65+

Sex: Any

Trial Phase: Phase < 1

Sponsor: The University of Texas Health Science Center at San Antonio

Must not be taking: Immunosuppressants, CYP3A4 drugs

Disqualifiers: Diabetes, Heart disease, Cancer, others

Compensation: Varies

Number of Visits: Unknown

194 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two drugs, Rapamycin and Everolimus, which might slow aging by adjusting cell functions to resemble those of younger individuals. Researchers aim to determine the optimal dose and timing for these drugs in healthy older adults. The trial compares daily and intermittent dosing with a placebo to identify the most effective method. Individuals aged 65 to 90, living independently, and in good overall health may qualify for this study. As an Early Phase 1 trial, this research seeks to understand how these treatments work in people, offering participants a chance to contribute to groundbreaking science.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking glucose-lowering medications, immunosuppressants, or drugs affecting certain liver enzymes. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both Rapamycin and Everolimus, the drugs in this study, have been tested in people before. Rapamycin has not yet been proven to extend human lifespan, but it has generally been safe for healthy individuals. Although no serious side effects have been directly linked to the drug, it has led to more infections, suggesting a potential impact on the immune system.

Everolimus is already approved for other uses, providing some reassurance about its safety. Studies have shown it is tolerable for older adults. Common side effects include mouth sores, fever, and cold-like symptoms, but these are usually manageable.

As this is an early phase trial, the main goal is to determine the best dose and schedule. Researchers are still learning how these drugs work in older adults. While some safety data exists from other uses, further research will help confirm the safety of these drugs for aging. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Rapamycin and Everolimus for tackling aging because these treatments work by targeting the mTOR pathway, which plays a crucial role in cell growth and aging processes. Unlike typical anti-aging strategies that focus on surface-level symptoms or lifestyle changes, these drugs aim to impact the biological mechanisms of aging directly. Rapamycin and Everolimus are distinct in their approach, as they potentially modify the aging process itself rather than just addressing age-related diseases individually. This innovative approach has the potential to not only slow down aging but also enhance overall health span, making it a groundbreaking area of study in the quest for healthier aging.

What evidence suggests that this trial's treatments could be effective for aging?

This trial will evaluate Rapamycin and Everolimus as separate treatments to assess their effects on aging. Studies have shown that Rapamycin can slow aging and help prevent age-related diseases. It improves health indicators such as the immune system and heart in animal studies. Many studies suggest that Rapamycin reduces cell aging and supports healthy aging. For Everolimus, early research indicates it might improve signs of aging by blocking a protein called mTORC1, which is linked to aging. Although more research is needed, both Rapamycin and Everolimus show promise in slowing aging processes in humans. ^{4 6 7 8 9}

Who Is on the Research Team?

Ellen Kraig, PhD

Principal Investigator

The University of Texas Health Science Center at San Antonio

Are You a Good Fit for This Trial?

This trial is for healthy older adults interested in participating in a study that aims to slow down the aging process. The focus is on finding safe dosages of drugs called mTOR inhibitors, which might help reduce age-related issues. Both men and women are encouraged to join.

Inclusion Criteria

I am part of the older cohort for Sub-study 2 or 3.

I am either a man or a woman.

Community-dwelling

Exclusion Criteria

I am eligible for the older cohort sub-studies.

I have a chronic inflammatory, autoimmune disease, or an ongoing infection.

Allergic to lidocaine

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment (Sub-study 2)

Short-term dose-finding study with mTOR inhibitors in older adults

6 weeks

Multiple visits for dose adjustment and monitoring

Follow-up (Sub-study 2)

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment (Sub-study 3)

Long-term clinical trial with daily and intermittent dosing of mTOR inhibitors

6 months

Regular visits for monitoring and assessments

Follow-up (Sub-study 3)

Participants are monitored for safety and effectiveness after long-term treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus
• Rapamycin

Trial Overview The RESTOR trial is testing two mTOR inhibitor drugs, Rapamycin and Everolimus, against a placebo to see if they can safely mimic the cellular conditions of younger individuals in older adults, potentially slowing aging.

How Is the Trial Designed?

Group I: Aim 2: Sub-study 3 Optimized INTERMITTENT Dosing of an mTOR inhibitor Experimental Treatment 2 Interventions

Based on the findings from Aim 1, the optimal drug (RAPA or EVERO), interval between doses, and dose for INTERMITTENT delivery will be tested in a blinded placebo-controlled trial in older human subjects. The drug/dose/interval used in males may differ from the one used in females as the OD will be determined independently for the two sexes. PD parameters 'downstream' from mTOR will be followed. Although drug is delivered on an intermittent schedule, subjects will be given a pill each day (either drug or placebo, as scheduled) to maintain blinding.

Group II: Aim 2: Sub-study 3 Optimized DAILY Dose of an mTOR inhibitor Experimental Treatment 2 Interventions

Based on the findings from Aim 1, the optimal drug (RAPA or EVERO) and dose for DAILY delivery will be tested in a blinded placebo-controlled trial in older human subjects. The drug/dose used in males may differ from the one used in females as the OD will be determined independently for the two sexes. PD parameters 'downstream' from mTOR will be followed.

Group III: Aim 1:Sub-study 2 Intermittent dosing Cohort Rapamycin Experimental Treatment 1 Intervention

Aim 1 is an open label, adaptive, dose finding PK/PD trial in older women and men. In sub-study 2 (part of Aim 1), an older cohort will be studied to determine the optimal dose (OD) in milligrams and the optimal interval for intermittent delivery of rapamycin (RAPA) based on changes in PD parameters 'downstream' from mTOR. Based on the data acquired, additional older cohorts will be tested at higher/lower doses in an adaptive, step-wise trial design.

Group IV: Aim 1:Sub-study 2 Daily dosing Cohort Rapamycin Experimental Treatment 1 Intervention

Aim 1 is an open label, adaptive, dose finding PK/PD trial in older women and men. In sub-study 2 (part of Aim 1), an older cohort will be studied to determine the optimal dose (OD) in milligrams of rapamycin (RAPA) based on changes in PD parameters 'downstream' from mTOR. Based on the data acquired, additional older cohorts will be tested at higher/lower doses in an adaptive, step-wise trial design.

Group V: Aim 1: Sub-study 2 Intermittent dosing Cohort Everolimus Experimental Treatment 1 Intervention

Aim 1 is an open label, adaptive, dose finding PK/PD trial in older women and men. In sub-study 2 (part of Aim 1), an older cohort will be studied to determine the optimal dose (OD) in milligrams and the optimal interval for intermittent delivery of everolimus (EVERO) based on changes in PD parameters 'downstream' from mTOR. Based on the data acquired, additional older cohorts will be tested at higher/lower doses in an adaptive, step-wise trial design.

Group VI: Aim 1: Sub-study 2 Daily dosing Cohort Everolimus Experimental Treatment 1 Intervention

Aim 1 is an open label, adaptive, dose finding PK/PD trial in older women and men. In sub-study 2 (part of Aim 1), an older cohort will be studied to determine the optimal dose (OD) of everolimus (EVERO) in milligrams based on changes in PD parameters 'downstream' from mTOR. Based on the data acquired, additional older cohorts will be tested at higher/lower doses in an adaptive, step-wise trial design.

Group VII: Aim 2: Sub-study 3 Placebo control Placebo Group 1 Intervention

Daily administration of a placebo will be given to a cohort of older human subjects. Both males and females will be enrolled as controls.

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?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

Sirolimus is a powerful immunosuppressant used in kidney transplantation that works by inhibiting the mTOR pathway, which is crucial for cell growth and proliferation, leading to reduced rates of acute rejection episodes to less than 10% when combined with cyclosporin A (CsA).

In clinical trials, using sirolimus at doses of 2 or 5 mg/day alongside CsA and steroids resulted in acute rejection rates of only 19% and 14% within 12 months, while also potentially reducing the need for nephrotoxic calcineurin inhibitors, although it may cause side effects like myelosuppression and increased lipid levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. Kahan, BD.[2019]

In a phase 1 study involving 32 pediatric patients on dialysis, sirolimus was found to be well tolerated with no serious adverse events reported, indicating its safety for use in this population.

Younger patients (ages 5-11) showed significantly higher clearance rates of sirolimus compared to older patients (ages 12-18), suggesting they may need higher maintenance doses to achieve similar drug levels as healthy adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of ascending single doses of sirolimus (Rapamune, rapamycin) in pediatric patients with stable chronic renal failure undergoing dialysis. Tejani, A., Alexander, S., Ettenger, R., et al.[2022]

Everolimus, an oral mTOR inhibitor, significantly improves progression-free survival in patients with clear cell renal cancer, increasing it from a median of 1.9 months to 4.9 months in a phase III trial with a hazard ratio of 0.33 (P < 0.001).

The treatment is generally well-tolerated, with mild to moderate side effects that can be managed, and it has been approved as a validated option for patients who have progressed on VEGFR inhibitors, with ongoing trials exploring its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Coppin, C.[2021]

In kidney transplant recipients, using target of rapamycin inhibitors (TOR-I) instead of calcineurin inhibitors (CNI) did not change the rate of acute rejection but resulted in lower serum creatinine levels, indicating better kidney function.

When TOR-I replaced antimetabolites, there was a reduction in acute rejection and cytomegalovirus infections, although it increased the risk of hypercholesterolemia, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. Webster, AC., Lee, VW., Chapman, JR., et al.[2021]

Sirolimus (rapamycin) is an effective immunosuppressant approved for preventing graft rejection in kidney transplants, with a lower risk of complications compared to other immunosuppressants.

Recent findings suggest that sirolimus may also have potential in treating skin disorders and extending lifespan, making it a promising candidate for addressing age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. Peters, T., Traboulsi, D., Tibbles, LA., et al.[2014]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05835999

Study Details | NCT05835999 | Everolimus Aging Study The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/22297244/

Efficacy and safety of everolimus in elderly patients with ... Conclusions: Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity ...

3. withpower.com withpower.com/trial/phase-2-insulin-resistance-2-2023-c7d10

Everolimus for Aging (EVERLAST Trial) Early findings suggest that by blocking mTORC1, everolimus might improve signs of aging in humans. Although more research is needed specifically on aging, these ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05835999?term=mTOR&aggFilters=status:rec&rank=4

Everolimus Aging Study (EVERLAST) The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1550413123004588

Human trials exploring anti-aging medicines Here, we summarize the current knowledge on eight promising drugs and natural compounds that have been tested in the clinic.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2012/022334s016lbl.pdf

AFINITOR (everolimus) tablets - accessdata.fda.gov The median age of patients was 61 years (range 28-93), and 75% were. Caucasian. Safety results are based on a median follow-up of approximately 13 months. The ...

7. ema.europa.eu ema.europa.eu/en/documents/product-information/votubia-epar-product-information_en.pdf

Votubia, INN-everolimus - European Medicines Agency The most frequent adverse reactions (incidence ≥1/10) from the pooled safety data are (in decreasing order): stomatitis, pyrexia, nasopharyngitis ...

8. mayoclinic.org mayoclinic.org/drugs-supplements/everolimus-oral-route/description/drg-20072842

Everolimus (oral route) - Side effects & dosage Safety and efficacy have not been established. ... Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the ...

9. novartis.com novartis.com/us-en/sites/novartis_us/files/afinitor.pdf

afinitor.pdf ... age, while 7% were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients. 8.6. Hepatic ...