Rapalog Pharmacology (RAP PAC) Study

NCT05949658 | Recruiting Phase 1 FDA Drug

• 4 other identifiers: 2023-02751U01AG081482-01SMPH/MEDICINE/GER-AD DEVProtocol Version 1/30/2025
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of RAP PAC is to identify safe and effective weekly dose(s) for the mTOR inhibitors sirolimus and everolimus that intervene on the underlying fundamental biology of aging. Participants who are 55-89 years old that are free of overt chronic diseases will be assigned to either 6 weeks of sirolimus or everolimus (5 mg, 10 mg, or 15 mg once per week). The investigators will complete the everolimus arm first and then subsequently complete the sirolimus arm of the study. Total time on study would be up to 17 weeks to complete baseline and follow up visits.

Conditions

Aging

Keywords

Rapamycin; Rapamycin analog; mTOR; mTOR inhibitor; sirolimus; everolimus; rapamune

Outcome Measures

Primary Outcomes (1)

• Dose Limited Toxicities (DLTs)

  A recommended phase 2 dose (RP2D) will be determined through evaluating dose limiting toxicities (DLT), which is defined as ≥Grade 2 adverse event following CTCAE v6.0.

  Through study completion, an average 3 years

Secondary Outcomes (13)

• Time course of drug concentration in blood

  First dose to 168 hours post dose

• Time course of drug concentration in blood

  First dose to 168 hours post dose

• Change in mTOR signaling in blood and muscle

  0 (pre-intervention) and 6 weeks (post-intervention)

• Change in concentration of metabollites

  0 (pre-intervention) and 6 weeks (post-intervention)

• Change in concentration of lipid species

  0 (pre-intervention) and 6 weeks (post-intervention)

Study Arms (2)

Sirolimus

EXPERIMENTAL

1mg tablets of sirolimus that total the assigned dose

Drug: Sirolimus

Everolimus

EXPERIMENTAL

1mg tablets of everolimus that total the assigned dose

Drug: Everolimus

Interventions

Sirolimus DRUG

5mg, 10mg, or 15mg once weekly sirolimus

Also known as: Rapamycin

Sirolimus

Everolimus DRUG

5mg, 10mg, or 15mg once weekly everolimus

Everolimus

Eligibility Criteria

• Age: 55 Years - 89 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Middle-age adults free of overt chronic disease
• Willing to provide informed consent
• Willing to comply with all study procedures and be available for the duration of the study
• Able to use and be contacted by telephone
• Ability to take oral medication
• Not planning to change diet or physical activity status
• Adequate organ function as indicated by standard laboratory tests: hematology (complete blood count), and clinical chemistry
• Males must agree to avoid impregnation of women during and for four weeks after completing study visits through use of an acceptable method of contraception

You may not qualify if:

• Heart disease (history, abnormal ECG)
• Cerebrovascular disease (history)
• Cancer or less than 5 years in remission (history)
• Chronic respiratory disease (history, FEV1/FVC \< 70, FEV1 \< 80% predicted)
• Chronic liver disease (history, abnormal blood liver panel, ALT \>104 IU/L, AST \>80 IU/L)
• Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, OGTT ≥ 200 mg/dl at 2 hrs.)
• Alzheimer's (history)
• Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine\>1.4, eGFR≤60 ml/min/1.73m2)
• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
• Taking azathioprine (Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), dexamethasone (Decadron, Dexpak), methotrexate (Rheumatrex, Trexall), prednisolone (Orapred, Pediapred, Prelone), prednisone (Sterapred), sirolimus (Rapamune), and tacrolimus (Prograf) or other medications proposed to lower the immune system
• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors such as ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem
• Taking strong CYP3A4 activators such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital
• Subjects who are not willing to restrict the use of grapefruit, grapefruit juice, cannabidiol (CBD) and other foods/substances that are known to inhibit cytochrome P450 and PgP activity and may increase everolimus exposures and should be avoided during treatment
• Subjects who are not willing to restrict the use of St. John's Wort (Hypericum perforatum) because it may decrease everolimus exposure unpredictably.
• Subjects who are not willing to avoid blood donations 8 weeks prior to the first visit and 8 weeks after the last visit

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• National Institute on Aging (NIA): collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (1)

University of Wisconsin

Madison, Wisconsin, 53705, United States

RECRUITING

MeSH Terms

Interventions

Sirolimus; Everolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Adam Konopka, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Brittany Grasso

CONTACT

608-263-2386; rap_pac@medicine.wisc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The Bayesian Optimal Interval Design (BOIN) will be used to perform a phase I, dose finding trial in healthy older men and women (55-89yrs) for the mTOR inhibitors sirolimus and everolimus. Middle-aged to older adults will be treated with either sirolimus or everolimus for 6 weeks. All participants will take one capsule weekly. This dose escalation trial will begin with two cohorts, each consisting of 3 male and 3 female participants. The first two cohorts will take a weekly 5mg dose of sirolimus or a weekly 5mg dose of everolimus. Researchers will enroll for both arms of the study concurrently. Participants will be informed that they will be allocated to the next available opening that works with their schedule, which could be either everolimus or rapamycin. The dose can be escalated/de-escalated from the current dose based on the rate of dose limited toxicity (DLT) at the end of the 6-week intervention for each cohort. The 15mg dose will be the highest dose possible in this trial.

Study Record Dates

• First Submitted: June 26, 2023
• First Posted: July 18, 2023
• Study Start: May 15, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): December 1, 2028
• Last Updated: February 10, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data from this study may be requested from other researchers years after the completion of the study endpoints by contacting Dr. Adam Konopka or the NIA BioBank Repository.

Locations

US (1)