Rapamycin + Everolimus for Aging

(RESTOR Trial)

Overseen By Ellen Kraig, 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

Trial Summary

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.

What data supports the effectiveness of the drug Rapamycin + Everolimus for aging?

Everolimus and sirolimus (rapamycin) are known to inhibit mTOR, a protein that plays a role in cell growth and aging. Sirolimus has shown promise in extending lifespan in mice and treating age-related skin conditions, suggesting potential benefits for aging. ^{1 2 3 4 5}

Is Rapamycin + Everolimus safe for humans?

Everolimus and sirolimus (rapamycin) have been used safely in humans for conditions like kidney transplants and certain cancers. They are known to be effective immunosuppressants with a lower risk of some complications compared to other drugs, but safety assessments should consider potential side effects and individual health conditions. ^{1 2 3 4 5}

What makes the drug Rapamycin + Everolimus unique for aging?

Rapamycin and Everolimus are unique because they are both inhibitors of the mammalian target of rapamycin (mTOR), a pathway involved in cell growth and aging. This combination is novel for aging as it targets a specific biological pathway that is not typically addressed by other treatments. ^{1 2 3 4 6}

What is the purpose of this trial?

As people get older, there are changes in their cells and tissues that may affect their ability to function. This can lead to increased death and age-associated disorders, like heart disease, cancer, and Alzheimer's disease. Studies in animal models have been able to identify drugs that slow the aging process, leading to a longer, healthier life. This study is focused on one such family of drugs, called mTOR inhibitors, and the investigators' goal is to test two of these drugs, Rapamycin (Sirolimus) and Everolimus (Afinitor), in healthy older adults to find a dose and dose timing that can be used to safely inhibit mTOR to the levels seen in young healthy persons. The investigators expect that the dose that works well in women may differ from the one that is best in men, so it is important to include both sexes in this research.

Research Team

Ellen Kraig, PhD

Principal Investigator

The University of Texas Health Science Center at San Antonio

Eligibility Criteria

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.

Fully vaccinated against COVID19

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

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

Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. [2021]

2. Denmark 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. [2022]

3. New Zealand pubmed.ncbi.nlm.nih.gov

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

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

A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial. [2023]

5. Canada pubmed.ncbi.nlm.nih.gov

Sirolimus: a therapeutic advance for dermatologic disease. [2014]

6. England pubmed.ncbi.nlm.nih.gov

Sirolimus: a comprehensive review. [2019]