Everolimus Aging Study

Study Overview
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Brief Summary
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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
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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.

Official Title
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Clinical Evaluation of mTORC1 Inhibition for Geroprotection

Conditions
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Aging, Insulin Resistance

Intervention / Treatment
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* Drug: Everolimus 0.5 MG once per day
* Drug: Everolimus 5 MG once per week
* Drug: Placebo once per day
* Drug: Placebo once per week


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daily Everolimus (0.5 mg/day) and Weekly Placebo<br>Once daily (0.5 mg) everolimus and once weekly placebo taken orally for 24 weeks | Drug: Everolimus 0.5 MG once per day<br>* Everolimus is considered an mTOR kinase inhibitor<br>Drug: Placebo once per week<br>* No therapeutic effect<br>|
| Experimental: Daily Placebo and Weekly Everolimus (5mg/week)<br>Once daily placebo and once weekly (5 mg) everolimus taken orally for 24 weeks | Drug: Everolimus 5 MG once per week<br>* Everolimus is considered an mTOR kinase inhibitor<br>Drug: Placebo once per day<br>* No therapeutic effect<br>|
| Placebo Comparator: Daily Placebo and Weekly Placebo<br>Once daily placebo and once weekly placebo taken orally for 24 weeks | Drug: Placebo once per day<br>* No therapeutic effect<br>Drug: Placebo once per week<br>* No therapeutic effect<br>|
| No Intervention: Young Adult Reference Group<br>Baseline testing only | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| 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 | 
| 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) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rapamycin, rapamycin analog, mTOR, everolimus