RESTOR: PK/PD mTORi Inhibition in Older Adults

NCT06658093 | Recruiting Early Phase 1 DMC FDA Drug

• 2 other identifiers: STUDY00000471U01AG089242
• Study Type: interventional
• Target: 194
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Aging

Keywords

mTOR inhibitors

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetics (PK) of mTOR inhibitor in blood

  The levels of the study drug will be measured in whole blood

  Baseline to study end (approximately 12 months for Aim 2; 12 weeks for Aim 1)

• PD measure of inhibition of mTOR activity in blood cells - p-rpS6

  Proteins prepared from PBMCs (peripheral blood mononuclear cells) will be analyzed for phosphorylation of ribosomal protein S6, downstream of mTORC1.

  Baseline to study end (approximately 12 months for Aim 2; 12 weeks for Aim 1)

• Level of Soluble Intercellular Adhesion Molecule-1 (sICAM-1)

  The level of soluble (s)ICAM-1 will be measured in serum.

  Baseline to study end (approximately 12 months)

Secondary Outcomes (10)

• PK of mTOR inhibitor in fat (Aim 2 only)

  Baseline and study end (approximately 12 months)

• PK of mTOR inhibitor in muscle (Aim 2 only)

  Baseline to study end (approximately 12 months)

• PD measure of inhibition of mTOR activity in fat cells (Aim 2 only) - pS6K

  Baseline to study end (approximately 12 months)

• PD measure of inhibition of mTOR activity in muscle (Aim 2 only) - pS6K

  Baseline to study end (approximately 12 months)

• PD measure of inhibition of mTOR activity in PBMCs, S6-kinase

  Baseline to study end (approximately 12 months)

Study Arms (7)

Aim 1:Sub-study 2 Daily dosing Cohort Rapamycin

EXPERIMENTAL

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

Aim 1: Sub-study 2 Daily dosing Cohort Everolimus

EXPERIMENTAL

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

Aim 1:Sub-study 2 Intermittent dosing Cohort Rapamycin

EXPERIMENTAL

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

Aim 1: Sub-study 2 Intermittent dosing Cohort Everolimus

EXPERIMENTAL

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

Aim 2: Sub-study 3 Optimized DAILY Dose of an mTOR inhibitor

EXPERIMENTAL

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; Drug: Everolimus

Aim 2: Sub-study 3 Optimized INTERMITTENT Dosing of an mTOR inhibitor

EXPERIMENTAL

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; Drug: Everolimus

Aim 2: Sub-study 3 Placebo control

PLACEBO COMPARATOR

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

Interventions

Rapamycin DRUG

mTOR inhibitor

Also known as: RAPA

Aim 1:Sub-study 2 Daily dosing Cohort Rapamycin; Aim 1:Sub-study 2 Intermittent dosing Cohort Rapamycin; Aim 2: Sub-study 3 Optimized DAILY Dose of an mTOR inhibitor; Aim 2: Sub-study 3 Optimized INTERMITTENT Dosing of an mTOR inhibitor

Everolimus DRUG

mTOR inhibitor

Also known as: EVERO

Aim 1: Sub-study 2 Daily dosing Cohort Everolimus; Aim 1: Sub-study 2 Intermittent dosing Cohort Everolimus; Aim 2: Sub-study 3 Optimized DAILY Dose of an mTOR inhibitor; Aim 2: Sub-study 3 Optimized INTERMITTENT Dosing of an mTOR inhibitor

Placebo OTHER

Inert placebo for rapamycin or everolimus

Also known as: Placebo capsule

Aim 2: Sub-study 3 Placebo control

Eligibility Criteria

• Age: 65 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Older Cohort Sub-study 2 (AIM 1) and Sub-study 3 (AIM 2):
• Resident of nursing home or long-term care facility
• Subjects with diabetes or currently taking glucose lowering medications
• 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
• Active cancer or history of cancer treatment within the last 5 years
• 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)
• History of a coagulopathy or any medical condition requiring anticoagulation (except low dose ASA)
• Renal insufficiency with an estimated glomerular filtration rate of \<30ml/min
• Uncontrolled hypercholesterolemia \>350mg/dl or uncontrolled hypertriglyceridemia \>500mg/dl
• 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
• History of skin ulcers or poor wound healing
• Active tobacco use (within 6 months)
• 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
• Liver disease
• Systemic treatment with an immunosuppressant (prednisone, etc.) within the year prior to enrollment

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead
• National Institute on Aging (NIA): collaborator

Study Sites (1)

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

RECRUITING

Related Publications (1)

• Kraig E, Linehan LA, Liang H, Romo TQ, Liu Q, Wu Y, Benavides AD, Curiel TJ, Javors MA, Musi N, Chiodo L, Koek W, Gelfond JAL, Kellogg DL Jr. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol. 2018 May;105:53-69. doi: 10.1016/j.exger.2017.12.026. Epub 2018 Feb 3.

  PMID: 29408453 BACKGROUND

MeSH Terms

Interventions

Sirolimus; Everolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Ellen Kraig, PhD

  The University of Texas Health Science Center at San Antonio

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dean L Kellogg, Jr, MD PhD

CONTACT

(210) 617 5197; kelloggd@uthscsa.edu

Ellen Kraig, PhD

CONTACT

(210) 367-3171; kraig@uthscsa.edu

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: Blinding will only occur in Aim 2 (Sub-study 3). Randomization will be done by the research pharmacy providing the investigational drug.
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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

Study Record Dates

• First Submitted: October 22, 2024
• First Posted: October 26, 2024
• Study Start: August 13, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028
• Last Updated: September 4, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: At the time of publication in a peer review journal

Locations

US (1)