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Purpose

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.

Condition

Eligibility

Eligible Ages
Between 65 Years and 90 Years
Eligible Sex
All
Accepts Healthy Volunteers
Yes

Inclusion Criteria

Older Cohort Sub-study 2 (AIM 1) and Sub-study 3 (AIM 2): 1. Age ≥65 to 90 years 2. Men and women 3. In good health with all medical problems stable. 4. Community-dwelling 5. Agreement to adhere to Lifestyle Considerations throughout study duration. 6. Ability of participant to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

Older Cohort Sub-study 2 (AIM 1) and Sub-study 3 (AIM 2): 1. Resident of nursing home or long-term care facility 2. Subjects with diabetes or currently taking glucose lowering medications 3. History of moderate-severe heart disease (New York Heart Classification greater than grade II) or pulmonary disease (dyspnea on exertion upon climbing one flight of stairs or less; abnormal breath sounds on auscultation); Moderate to severe valvular heart disease 4. Active cancer or history of cancer treatment within the last 5 years 5. Chronic inflammatory condition, autoimmune disease, or infectious processes (e.g., active tuberculosis, HIV, rheumatoid arthritis, systemic lupus erythematosus, acute or chronic hepatitis B or C) 6. History of a coagulopathy or any medical condition requiring anticoagulation (except low dose ASA) 7. Renal insufficiency with an estimated glomerular filtration rate of <30ml/min 8. Uncontrolled hypercholesterolemia >350mg/dl or uncontrolled hypertriglyceridemia >500mg/dl 9. Anemia or abnormal blood cell counts: hemoglobin level <9.0g.dl; white blood count <3500/mm3; neutrophil count <2000/ mm3; platelet count <125,000/mm3 10. History of skin ulcers or poor wound healing 11. Active tobacco use (within 6 months) 12. Diagnosis of any disabling neurologic disease such as Parkinson's Disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, cerebrovascular accident with residual deficits (muscle weakness or gait disorder), severe neuropathy, diagnosis of dementia or Clox1 score less than 10 at the time of screening visit, cognitive impairment due to any reason such that the patient is unable to provide informed consent 13. Liver disease 14. Systemic treatment with an immunosuppressant (prednisone, etc.) within the year prior to enrollment 15. Treatment with drugs known to affect cytochrome P450 (CYP3A4), i.e., diltiazem, erythromycin. 16. Patients with history of recent (within 6 months) myocardial infarction or active coronary disease 17. Patients with history of recent (within 6 months) intestinal disorders 18. History of severe head trauma, brain injury, brain surgery, inflammation of the brain, or history of seizure disorder 19. History of Long-Covid (PASC) within one year 20. Acute Covid19 or Covid19 infection within the last 6 months 21. Unwilling to forgo grapefruit juice consumption. 22. Participation in mTORi study within the prior year. (Note: participants in AIM 1 will be excluded from participating in AIM 2 of the proposed trial.) 23. Allergic to RAPA or EVERO 24. Allergic to lidocaine 25. Recreational drug use 26. Donated blood over a two-month period prior to study initiation. 27. Currently using cannabidiol (CBD) or tetrahydrocannabinol (THC) or any preparation contained these, or related, substances. 28. Currently using hormone replacement or modulating therapies.

Study Design

Phase
Early Phase 1
Study Type
Interventional
Allocation
Randomized
Intervention Model
Sequential Assignment
Intervention Model Description
A single site open label adaptive clinical trial (Aim 1:Sub-study 2) followed by a placebo-controlled blinded clinical trial (Aim 2) to optimize the use of mTOR inhibitors in older persons a functions of drug, dose, dosing schedule and sex. It will be carried out in 2 sub-studies: Aim 1: -Sub-study 2: Comparison of 2 mTOR inhibitors in an adaptive open-label dose finding pharmacokinetic/pharmacodynamic study Aim 2: Sub-study 3: Assess the safety/tolerability/adverse events of optimized dose of mTOR inhibitors in daily vs intermittent dosing
Primary Purpose
Basic Science
Masking
Double (Participant, Care Provider)
Masking Description
Blinding will only occur in Aim 2 (Sub-study 3). Randomization will be done by the research pharmacy providing the investigational drug.

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Aim 1:Sub-study 2 Daily dosing Cohort Rapamycin 		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.
  • Drug: Rapamycin
    mTOR inhibitor
    Other names:
    • RAPA
Experimental
Aim 1: Sub-study 2 Daily dosing Cohort Everolimus 		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.
  • Drug: Everolimus
    mTOR inhibitor
    Other names:
    • EVERO
Experimental
Aim 1:Sub-study 2 Intermittent dosing Cohort Rapamycin 		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.
  • Drug: Rapamycin
    mTOR inhibitor
    Other names:
    • RAPA
Experimental
Aim 1: Sub-study 2 Intermittent dosing Cohort Everolimus 		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.
  • Drug: Everolimus
    mTOR inhibitor
    Other names:
    • EVERO
Experimental
Aim 2: Sub-study 3 Optimized DAILY Dose of an mTOR inhibitor 		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.
  • Drug: Rapamycin
    mTOR inhibitor
    Other names:
    • RAPA
  • Drug: Everolimus
    mTOR inhibitor
    Other names:
    • EVERO
Experimental
Aim 2: Sub-study 3 Optimized INTERMITTENT Dosing of an mTOR inhibitor 		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.
  • Drug: Rapamycin
    mTOR inhibitor
    Other names:
    • RAPA
  • Drug: Everolimus
    mTOR inhibitor
    Other names:
    • EVERO
Placebo Comparator
Aim 2: Sub-study 3 Placebo control 		Daily administration of a placebo will be given to a cohort of older human subjects. Both males and females will be enrolled as controls.
  • Other: Placebo
    Inert placebo for rapamycin or everolimus
    Other names:
    • Placebo capsule

Recruiting Locations

The University of Texas Health Science Center at San Antonio
San Antonio 4726206, Texas 4736286 78229
Contact:
Dean L Kellogg Jr.,, MD PhD
210-617-5197
kelloggd@uthscsa.edu

More Details

Status
Recruiting
Sponsor
The University of Texas Health Science Center at San Antonio

Study Contact

Dean L Kellogg, Jr, MD PhD
(210) 617 5197
kelloggd@uthscsa.edu

Detailed Description

The study will be done in three parts, each with different human subject groups. Participants may only enroll in one of the sub-studies. Sub-study 1: Determining target mTOR activity values in YOUNG untreated subjects (ages 20-30 years): NOTE: This aim of the study is not a clinical trial, so this population will not be included in participant flow or included as an arm in the study. This study defines "best dose" as the choice of drug, dose, and frequency that will come closest to restoring the "youthful" levels of mTOR activity in an older individual. The investigators first need to measure mTOR activity in young untreated subjects to define these target "youthful" mTOR activity levels. Sub-study 2. Finding the most effective drug, dose, and timing for dosing for oral dosing of the mTOR inhibitor drugs in older adults (65-90 years): Healthy older persons will be recruited for a short-term (6 week treatment plus 4 week follow-up) dose-finding study. The most effective, but safe dose will then be tested in a larger number of subjects in Sub-study 3. Importantly, the best drug and dose regimen for females may differ from the one determined for males so the cohort will include both sexes. Sub-study 3. Placebo controlled trial testing of DAILY (sustained) vs. INTERMITTENT mTOR inhibition in older human males and females: Sub-study 3 will enroll healthy older persons (65-90 yrs) for a long-term clinical trial (6 months of treatment plus 6 months of follow-up) with 3 test groups: i) best DAILY dose/drug; ii) best INTERMITTENT dose/drug/interval, and iii) PLACEBO (a pill that looks identical to the medicine, but has no drug in it). This study will help find out what effects, good and/or bad, Rapamycin or Everolimus have on older people who take the drug for a longer period of time. The safety of Rapamycin and Everolimus in humans has been tested in prior research studies; however, some side effects may not yet be known in healthy older persons. By completing the entire study, the Research Team hopes to learn more about how older human subjects can best be treated using these drugs (mTOR inhibitors) to help them live longer, healthier lives.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.