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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05949658
Other study ID # 2023-0275
Secondary ID 1U01AG081482-01S
Status Recruiting
Phase Phase 1
First received
Last updated
Start date May 15, 2024
Est. completion date December 2028

Study information

Verified date May 2024
Source University of Wisconsin, Madison
Contact Brittany Grasso
Phone 608-263-2386
Email rap_pac@medicine.wisc.edu
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 72
Est. completion date December 2028
Est. primary completion date March 2027
Accepts healthy volunteers Accepts Healthy Volunteers
Gender All
Age group 55 Years to 89 Years
Eligibility 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 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 - 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 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 Design


Related Conditions & MeSH terms


Intervention

Drug:
Sirolimus
5mg, 10mg, or 15mg once weekly sirolimus
Everolimus
5mg, 10mg, or 15mg once weekly everolimus

Locations

Country Name City State
United States University of Wisconsin Madison Wisconsin

Sponsors (3)

Lead Sponsor Collaborator
University of Wisconsin, Madison National Institute on Aging (NIA), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 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
Secondary 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
Secondary Change in mTOR signaling in blood and muscle To be evaluated through immunoblotting and immunoprecipitation 0 (pre-intervention) and 6 weeks (post-intervention)
Secondary 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)
Secondary 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)
Secondary Change in transcriptome Change in skeletal muscle and whole blood transcripts assessed via RNA sequencing 0 (pre-intervention) and 6 weeks (post-intervention)
Secondary Change in glucose tolerance Assess change in glucose tolerance by area under the curve 0 (pre-intervention) and 6 weeks (post-intervention)
Secondary Change in whole body insulin sensitivity Insulin sensitivity as assessed by the Matsuda Index. 0 (pre-intervention) and 6 weeks (post-intervention)
Secondary 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)
Secondary 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)
Secondary 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)
Secondary 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)
Secondary Change in insulin resistance Measured by change in homeostatic model of insulin resistance (HOMA-IR). 0 (pre-intervention) and 6 weeks (post-intervention)
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