Rapalog Pharmacology (RAP PAC) Study

Safer mTOR Inhibition for Human Geroprotection

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.

Study Overview

• Status: Recruiting
• Conditions: Aging
• Intervention / Treatment: Drug: Sirolimus; Drug: Everolimus

Detailed Description

The mTOR inhibitor rapamycin and rapamycin analogs (rapalogs) extend healthspan and/or lifespan in multiple model systems. However, the risk of adverse events and dose limiting toxicities in humans have thus far precluded the long-term prophylactic use of mTOR inhibitors as a therapy for aging and age-related diseases. The pharmacokinetics and pharmacodynamics (PK/PD) data for mTOR inhibitors in older adults is currently unknown and has prevented the identification of a safe dosage that could maximize health-span extension and minimize adverse effects.

RAP PAC will identify a recommended phase 2 trial dose for sirolimus and everolimus in older men and women by performing a phase 1, dose finding study that evaluates PK/PD, safety and tolerability, and mTOR signaling using conventional as well as novel approaches. Overall, the investigators will pair comprehensive molecular and pharmacologic approaches to evaluate PK/PD in humans and identify dosing regimens that safely inhibit mTOR complex 1 (mTORC1) to intervene in the biology of aging.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Brittany Grasso; Phone Number: 608-263-2386; Email: rap_pac@medicine.wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Recruiting
      • University of Wisconsin
      • Principal Investigator: Adam Konopka, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 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
• Taking daily NSAIDs such as ibuprofen, naproxen, aspirin and others, with the exception of baby aspirin (81mg)
• 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
• Low white-blood cell count (<4,000 cell/µL)
• History of stomatitis or ulcers in the mouth
• Those on glucose lowering drugs
• Participating in intensive exercise training program (high to moderate intensity exercise greater than 150 minutes per week) or planning to start new exercise program during study period
• Tobacco or nicotine use
• Allergies to lidocaine, sirolimus, or everolimus
• Subjects currently enrolled in other clinical trials. Subjects may be eligible after a washout period that will be reviewed on a case-by-case basis.
• Individuals with limited English proficiency
• Subjects who are planning to have elective surgery 12 weeks prior to or during the intervention

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sirolimus; 1mg tablets of sirolimus that total the assigned dose	Drug: Sirolimus; 5mg, 10mg, or 15mg once weekly sirolimus; Other Names: Rapamycin
Experimental: Everolimus; 1mg tablets of everolimus that total the assigned dose	Drug: Everolimus; 5mg, 10mg, or 15mg once weekly everolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time course of drug concentration in blood	Using PK parameters of Peak Plasma Concentration (Cmax, Cmin), determine duration of concentration of drug in blood measured pre dose, and 0.5, 1.5, 4, 48, and 168 hours post dose	First dose to 168 hours post dose
Time course of drug concentration in blood	Using PK parameters of Area under the plasma concentration versus time curve (AUC, T1/2), determine duration of concentration of drug in blood measured pre dose, and 0.5, 1.5, 4, 48, and 168 hours post dose	First dose to 168 hours post dose
Change in mTOR signaling in blood and muscle	To be evaluated through immunoblotting and immunoprecipitation	0 (pre-intervention) and 6 weeks (post-intervention)
Change in concentration of metabollites	Metabolomics: Change in concentration of blood and/or skeletal muscle metabolites as assessed by liquid chromatography mass spectrometry	0 (pre-intervention) and 6 weeks (post-intervention)
Change in concentration of lipid species	Lipidomics: Change in the concentration of lipid species in blood and/or skeletal muscle as assessed by liquid chromatography mass spectrometry	0 (pre-intervention) and 6 weeks (post-intervention)
Change in transcriptome	Change in skeletal muscle and whole blood transcripts assessed via RNA sequencing	0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose tolerance	Assess change in glucose tolerance by area under the curve	0 (pre-intervention) and 6 weeks (post-intervention)
Change in whole body insulin sensitivity	Insulin sensitivity as assessed by the Matsuda Index.	0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose variability	Glucose Variability will be assessed via continuous glucose monitoring during two occasions during weeks 0, and 6 by measuring the change in range.	0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose variability	Glucose Variability will be assessed via continuous glucose monitoring during two occasions during weeks 0, and 6 by measuring the change in total standard deviation.	0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose variability	Glucose Variability will be assessed via continuous glucose monitoring during two occasions during weeks 0, and 6 by measuring the change in mean daily differences (MODD).	0 (pre-intervention) and 6 weeks (post-intervention)
Change in glucose variability	Glucose Variability will be assessed via continuous glucose monitoring during two occasions during weeks 0, and 6 by measuring the change in the overall net glycemic action over a 4-h and 8-h period (CONGA4; CONGA8).	0 (pre-intervention) and 6 weeks (post-intervention)
Change in insulin resistance	Measured by change in homeostatic model of insulin resistance (HOMA-IR).	0 (pre-intervention) and 6 weeks (post-intervention)

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: National Institutes of Health (NIH); National Institute on Aging (NIA)
• Investigators: Principal Investigator: Adam Konopka, PhD, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: June 26, 2023
• First Submitted That Met QC Criteria: July 17, 2023
• First Posted (Actual): July 18, 2023

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: everolimus; Rapamycin; mTOR; sirolimus; mTOR inhibitor; Rapamycin analog; rapamune
• Additional Relevant MeSH Terms: Organic Chemicals; Macrolides; Lactones; Everolimus; Sirolimus
• Other Study ID Numbers: 2023-0275; SMPH/MEDICINE/GER-AD DEV (Other Identifier: UW Madison); 1U01AG081482-01 (U.S. NIH Grant/Contract); Protocol Version 4/10/2026 (Other Identifier: UW Madison)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No