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Everolimus Aging Study (EVERLAST)

Primary Purpose

Aging, Insulin Resistance

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Everolimus 0.5 MG once per day
Everolimus 5 MG once per week
Placebo once per day
Placebo once per week
Sponsored by
University of Wisconsin, Madison
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Aging focused on measuring rapamycin, rapamycin analog, mTOR, everolimus

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • University of Wisconsin-MadisonRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Placebo Comparator

No Intervention

Arm Label

Daily Everolimus (0.5 mg/day) and Weekly Placebo

Daily Placebo and Weekly Everolimus (5mg/week)

Daily Placebo and Weekly Placebo

Young Adult Reference Group

Arm Description

Once daily (0.5 mg) everolimus and once weekly placebo taken orally for 24 weeks

Once daily placebo and once weekly (5 mg) everolimus taken orally for 24 weeks

Once daily placebo and once weekly placebo taken orally for 24 weeks

Baseline testing only

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Cardiac Function: Change in fractional shortening velocity
Cardiac Function will be assessed by measuring the change in fractional shortening velocity determined during the echocardiogram.
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).
Safety: Number of Participants with Adverse Events
Safety will be measured in part by reporting the number of participants with adverse events.
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
Safety: Changes in concentration of blood lipids
Safety will be measured in part by reporting the changes in the concentration of blood lipids.
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
Safety: Changes in HbA1c (%)
Safety will be measured in part by reporting the changes in the percentage of glycosylated hemoglobin (Hba1c (%))
Safety: Changes in concentration of insulin
Safety will be measured in part by reporting the changes in fasting blood insulin concentration
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).

Full Information

First Posted
April 3, 2023
Last Updated
April 19, 2023
Sponsor
University of Wisconsin, Madison
Collaborators
National Institute on Aging (NIA)
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1. Study Identification

Unique Protocol Identification Number
NCT05835999
Brief Title
Everolimus Aging Study
Acronym
EVERLAST
Official Title
Clinical Evaluation of mTORC1 Inhibition for Geroprotection
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 24, 2023 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Wisconsin, Madison
Collaborators
National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aging, Insulin Resistance
Keywords
rapamycin, rapamycin analog, mTOR, everolimus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This is a randomized, placebo-controlled, double-blind, 24-week clinical trial using everolimus in middle-aged to older adults. This study will follow a "double-dummy" design where participants will be randomized 1:1:1 in a double-blinded fashion to one of three groups: 1) everolimus once daily (0.5 mg/day) plus placebo once weekly, 2) placebo once daily plus everolimus once weekly (5mg/week) or 3) placebo once daily and placebo once weekly. The double dummy design preserves the double-blind for both placebo versus everolimus and for daily versus weekly dosing schedules. Everolimus and placebo will be over encapsulated to be indistinguishable from one another. There will also be a group of young, healthy individuals who will complete baseline testing only and not the intervention. This group allows the determination if everolimus changes any molecular and physiological outcomes in older adults toward that of a young, healthy reference group.
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
86 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Daily Everolimus (0.5 mg/day) and Weekly Placebo
Arm Type
Experimental
Arm Description
Once daily (0.5 mg) everolimus and once weekly placebo taken orally for 24 weeks
Arm Title
Daily Placebo and Weekly Everolimus (5mg/week)
Arm Type
Experimental
Arm Description
Once daily placebo and once weekly (5 mg) everolimus taken orally for 24 weeks
Arm Title
Daily Placebo and Weekly Placebo
Arm Type
Placebo Comparator
Arm Description
Once daily placebo and once weekly placebo taken orally for 24 weeks
Arm Title
Young Adult Reference Group
Arm Type
No Intervention
Arm Description
Baseline testing only
Intervention Type
Drug
Intervention Name(s)
Everolimus 0.5 MG once per day
Intervention Description
Everolimus is considered an mTOR kinase inhibitor
Intervention Type
Drug
Intervention Name(s)
Everolimus 5 MG once per week
Intervention Description
Everolimus is considered an mTOR kinase inhibitor
Intervention Type
Drug
Intervention Name(s)
Placebo once per day
Intervention Description
No therapeutic effect
Intervention Type
Drug
Intervention Name(s)
Placebo once per week
Intervention Description
No therapeutic effect
Primary Outcome Measure Information:
Title
Metabolic Function: Change in peripheral insulin sensitivity
Description
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).
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Secondary Outcome Measure Information:
Title
Cardiac Function: Change in fractional shortening velocity
Description
Cardiac Function will be assessed by measuring the change in fractional shortening velocity determined during the echocardiogram.
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Cognitive Function: Change in cerebral blood flow
Description
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).
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Safety: Number of Participants with Adverse Events
Description
Safety will be measured in part by reporting the number of participants with adverse events.
Time Frame
up to 36 weeks
Title
Safety: Change in concentration of blood metabolites/enzymes
Description
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
Time Frame
0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
Title
Safety: Changes in concentration of blood lipids
Description
Safety will be measured in part by reporting the changes in the concentration of blood lipids.
Time Frame
0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
Title
Safety: Changes in number of blood cells
Description
Safety will be measured in part by reporting the changes in the number of blood cells as determined by blood cell count with differential
Time Frame
0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
Title
Safety: Changes in HbA1c (%)
Description
Safety will be measured in part by reporting the changes in the percentage of glycosylated hemoglobin (Hba1c (%))
Time Frame
pre-intervention baseline, post-intervention up to 24 weeks
Title
Safety: Changes in concentration of insulin
Description
Safety will be measured in part by reporting the changes in fasting blood insulin concentration
Time Frame
0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
Title
mTOR signaling: Change in phosphorylation of downstream targets of mTOR complex 1 and complex 2 as assessed by immunoblotting and immunoprecipitation.
Description
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).
Time Frame
pre-intervention baseline, post-intervention up to 24 weeks
Other Pre-specified Outcome Measures:
Title
Physical Function: Change in cardiorespiratory fitness
Description
Change in cardiorespiratory fitness defined as the VO2peak obtained during a graded exercise test on a stationary bicycle.
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Physical Function: Change in maximal knee extensor muscle power
Description
Change in maximal knee extensor muscle power obtained using dynamometry
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Physical Function: Change in maximal knee extensor muscle strength
Description
Change in maximal knee extensor muscle strength assessed by one repetition maximum (1-RM)
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Cognitive Function: Change in memory
Description
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.
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Cognitive Function: Change in learning
Description
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).
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Cognitive Function: Change in executive function
Description
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).
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Metabolic Function: Change in hepatic insulin sensitivity
Description
Change in hepatic insulin sensitivity as assessed by suppression of endogenous glucose production during the dual tracer, 75g oral glucose tolerance test (OGTT)
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Metabolic Function: Change in glucose variability
Description
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).
Time Frame
0 (pre-intervention), 12, and 24 weeks (post-intervention)
Title
Metabolic Function: Change in estimates of fasting insulin resistance
Description
Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Metabolic Function: Change in whole body insulin sensitivity.
Description
Change in Matsuda Index where a higher value indicates greater insulin sensitivity
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Metabolic Function: Change in insulin sensitivity and glucose clearance
Description
Change in oral glucose insulin sensitivity (OGIS) index where a higher value indicates greater insulin sensitivity
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Change in whole blood DNA Methylated positions
Description
Change in differentially methylated positions in whole blood samples as assessed by whole-genome sequencing
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Change in skeletal muscle transcriptome
Description
Transcriptomics: Change in skeletal muscle transcripts assessed via RNA sequencing
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Change in concentration of lipid species
Description
Lipidomics: Change in the concentration of lipid species in blood and/or skeletal muscle as assessed by liquid chromatography mass spectrometry
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Change in skeletal muscle protein abundance
Description
Proteomics: Change in abundance of skeletal muscle proteins as assessed by mass spectrometry.
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)
Title
Change in the concentration of metabolites
Description
Metabolomics: Change in concentration of blood and/or skeletal muscle metabolites as assessed by liquid chromatography mass spectrometry
Time Frame
0 (pre-intervention) and 24 weeks (post-intervention)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Everolimus Aging Study Team
Phone
608-256-1901
Email
everlast@medicine.wisc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adam Konopka, PhD
Organizational Affiliation
University of Wisconsin, Madison
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Wisconsin-Madison
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53705
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Adam Konopka
Phone
608-256-1901
Email
akonopka@medicine.wisc.edu

12. IPD Sharing Statement

Plan to Share 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.

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Everolimus Aging Study

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