Everolimus Aging Study

Aging Clinical Trial

— EVERLAST  

Official title:

Clinical Evaluation of mTORC1 Inhibition for Geroprotection

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05835999
• Other study ID #: 2021-1519
• Secondary ID: 1U01AG076941-01A
• Status: Recruiting
• Phase: Phase 2
• Start date: March 24, 2023
• Est. completion date: December 31, 2026

Study information

• Verified date: May 2024
• Source: University of Wisconsin, Madison
• Contact: Everolimus Aging Study Team
• Phone: 608-228-2978
• Email: everlast[@]medicine.wisc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve physiological and molecular hallmarks of aging in humans. Participants who are 55-80 years old and insulin resistant or prediabetic will be randomized to treatment and can expect to be on study for up to approximately 38 weeks. Participants aged 18-35 will not receive the intervention and can expect to be on study for up to approximately 8 weeks.

Description:

Pharmacological inhibition of mechanistic target of rapamycin (mTOR) has been repeatedly demonstrated to extend lifespan and prevent or delay several age-related diseases in diverse model systems. However, the risk of potentially serious side effects in humans have thus far prevented the long-term use of the mTOR inhibitor rapamycin as a therapy for aging and age-related diseases. Therefore, it remains unknown whether rapamycin or rapamycin analogs (rapalogs) can safely improve healthy aging in humans.

The objective of this project is to determine if 24 weeks of daily low dose (0.5 mg/day) or weekly intermittent (5 mg/week) treatment with the rapalog everolimus can safely improve physiological and molecular hallmarks of aging in middle-aged to older insulin resistant adults who are at high risk for nearly every age-related condition.

Using a double-blinded, randomized, placebo-controlled clinical trial, the investigators will perform a battery of gold-standard and innovative techniques to test the hypothesis that daily low dose or weekly everolimus treatment will improve 4 inter-related domains of physiological aging: metabolic, cardiac, cognitive, and physical function. The investigators will also assess the incidence of adverse events and changes from baseline blood chemistry, blood cell counts, lipids, glucose, and insulin.

To comprehensively examine the molecular target specificity and the impact on mechanisms of aging by everolimus, the team will evaluate mTORC1 and mTORC2 signaling, assess mitochondrial bioenergetics, and perform a multi-omics approach (epigenomics, transcriptomics, proteomics, lipidomics, and metabolomics) in blood and/or muscle biopsy samples.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 88
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria: Adults aged 55-80 years old

• 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 the telephone

• Ability to take oral medication

• Insulin Resistant defined by HOMA-IR greater than or equal to 1.5 or prediabetic defined as:

• impaired fasting glucose (100-125 mg/dL)

• HbA1c (5.7-6.4 percent)

• glucose 2 hours after a 75 gram oral glucose tolerance test (140-199 mg/dL)

• previous diagnosis of prediabetes in the past year

• Not planning to change diet or physical activity status

• Adequate organ function as indicated by standard laboratory tests: hematology (complete blood count), clinical chemistry and urinalysis

• Females of childbearing potential must have a negative urine pregnancy test before DEXA and before the oral glucose tolerance test (OGTT). A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

• Women of childbearing potential in sexual relationships with men must use an acceptable method of contraception from 30 days prior to enrollment until 4 weeks after completing study visits. 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.

• Note: Includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study enrollment), intercourse with men who underwent vasectomy.

Inclusion Criteria: Younger Adults aged 18-35 (No intervention)

• Free overt chronic disease

Exclusion Criteria:

• Pregnancy or breastfeeding

• Heart disease

• Cerebrovascular disease

• Cancer or less than 5 years in remission

• Chronic respiratory disease

• Chronic liver disease

• Diabetes

• Alzheimer's

• Chronic kidney disease

• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)

• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors

• Taking strong CYP3A4 activators

• Subjects who are not willing to restrict the use of grapefruit, grapefruit juice, and other foods 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

• Contraindications with MRI which could include metal on your body

• 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 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

Related Conditions & MeSH terms

• Aging
• Insulin Resistance

Intervention

Drug:
• Everolimus 0.5 MG once per day
Everolimus is considered an mTOR kinase inhibitor
• Everolimus 5 MG once per week
Everolimus is considered an mTOR kinase inhibitor
• Placebo once per day
No therapeutic effect
• Placebo once per week
No therapeutic effect

Locations

Country	Name	City	State
United States	University of Wisconsin-Madison	Madison	Wisconsin

Sponsors (2)

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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Physical Function: Change in cardiorespiratory fitness	Change in cardiorespiratory fitness defined as the VO2peak obtained during a graded exercise test on a stationary bicycle.	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Physical Function: Change in maximal knee extensor muscle power	Change in maximal knee extensor muscle power obtained using dynamometry	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Physical Function: Change in maximal knee extensor muscle strength	Change in maximal knee extensor muscle strength assessed by one repetition maximum (1-RM)	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Cognitive Function: Change in memory	Change in memory will be measured using the Montreal Cognitive Assessment (MoCA Test). Max score of 30. Score of 26 and above is considered normal.	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Cognitive Function: Change in learning	Change in learning via the California Verbal Learning Test-III: learning slope for trials 1-5 and long delay retention (score range 0-16, where higher scores are better).	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Cognitive Function: Change in executive function	Change in executive function will be measured using the Executive function as indexed by: the Delis-Kaplan Executive Function System Trails Test, and Color-Word Interference Test (score range 0-19, where higher scores are better).	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Metabolic Function: Change in hepatic insulin sensitivity	Change in hepatic insulin sensitivity as assessed by suppression of endogenous glucose production during the dual tracer, 75g oral glucose tolerance test (OGTT)	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Metabolic Function: Change in glucose variability	Glucose Variability will be assessed via continuous glucose monitoring during three occasions during weeks 0, 12, and 24 by measuring the change in range, total standard deviation, mean daily differences (MODD), and the overall net glycemic action over a 4-h and 8-h period (CONGA4; CONGA8).	0 (pre-intervention), 12, and 24 weeks (post-intervention)
Other	Metabolic Function: Change in estimates of fasting insulin resistance	Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Metabolic Function: Change in whole body insulin sensitivity.	Change in Matsuda Index where a higher value indicates greater insulin sensitivity	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Metabolic Function: Change in insulin sensitivity and glucose clearance	Change in oral glucose insulin sensitivity (OGIS) index where a higher value indicates greater insulin sensitivity	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Change in whole blood DNA Methylated positions	Change in differentially methylated positions in whole blood samples as assessed by whole-genome sequencing	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Change in skeletal muscle transcriptome	Transcriptomics: Change in skeletal muscle transcripts assessed via RNA sequencing	0 (pre-intervention) and 24 weeks (post-intervention)
Other	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 24 weeks (post-intervention)
Other	Change in skeletal muscle protein abundance	Proteomics: Change in abundance of skeletal muscle proteins as assessed by mass spectrometry.	0 (pre-intervention) and 24 weeks (post-intervention)
Other	Change in the concentration of metabolites	Metabolomics: Change in concentration of blood and/or skeletal muscle metabolites as assessed by liquid chromatography mass spectrometry	0 (pre-intervention) and 24 weeks (post-intervention)
Primary	Metabolic Function: Change in peripheral insulin sensitivity	Change (pre to post) in peripheral insulin sensitivity measured by glucose disposal rate relative to circulating insulin during a dual tracer 75g oral glucose tolerance test (OGTT).	0 (pre-intervention) and 24 weeks (post-intervention)
Secondary	Cardiac Function: Change in fractional shortening velocity	Cardiac Function will be assessed by measuring the change in fractional shortening velocity determined during the echocardiogram.	0 (pre-intervention) and 24 weeks (post-intervention)
Secondary	Cognitive Function: Change in cerebral blood flow	Change in blood flow in posterior cingulate, medial temporal lobe (hippocampus and parahippocampus) and inferior frontal cortex assessed by brain MRI (4D Flow, Arterial Spin Labeling).	0 (pre-intervention) and 24 weeks (post-intervention)
Secondary	Safety: Number of Participants with Adverse Events	Safety will be measured in part by reporting the number of participants with adverse events.	up to 36 weeks
Secondary	Safety: Change in concentration of blood metabolites/enzymes	Safety will be measured in part by reporting the change in the blood concentration of metabolites and enzymes as assessed by a complete metabolic panel	0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
Secondary	Safety: Changes in concentration of blood lipids	Safety will be measured in part by reporting the changes in the concentration of blood lipids.	0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
Secondary	Safety: Changes in number of blood cells	Safety will be measured in part by reporting the changes in the number of blood cells as determined by blood cell count with differential	0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
Secondary	Safety: Changes in HbA1c (%)	Safety will be measured in part by reporting the changes in the percentage of glycosylated hemoglobin (Hba1c (%))	pre-intervention baseline, post-intervention up to 24 weeks
Secondary	Safety: Changes in concentration of insulin	Safety will be measured in part by reporting the changes in fasting blood insulin concentration	0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
Secondary	mTOR signaling: Change in phosphorylation of downstream targets of mTOR complex 1 and complex 2 as assessed by immunoblotting and immunoprecipitation.	mTOR signaling will be assessed by measuring the change in phosphorylation of downstream targets of mTOR complex 1 and complex 2 via immunoblotting in muscle and/or peripheral mononuclear blood cells (PMBCs).	pre-intervention baseline, post-intervention up to 24 weeks