Clinical trial NCT05835999: Everolimus Aging Study
Official title: Clinical Evaluation of mTORC1 Inhibition for Geroprotection
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Aging
Insulin Resistance
Keywords: rapamycin
rapamycin analog
mTOR
everolimus
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2023-05-01
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

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 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. Daily use of high potency topical corticosteroids used on greater than or equal to 10% of body surface area will not be eligible. Nasal sprays or inhaled corticosteroids will be reviewed on a case-by-case basis.
* Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors
* Taking strong CYP3A4 activators
* Taking daily NSAIDs with the exception of baby asprin (81 mg)
* 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
* For those undergoing MRI, 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
* Subjects who are planning to have elective surgery 12 weeks prior to or during the intervention

Primary outcomes:
measure: Metabolic Function: Change in peripheral insulin sensitivity
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
Secondary outcomes:
measure: Cardiac Function: Change in fractional shortening velocity
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Cognitive Function: Change in cerebral blood flow
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Safety: Number of Participants with Adverse Events
timeFrame: up to 36 weeks
measure: Safety: Change in concentration of blood metabolites/enzymes
timeFrame: 0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
measure: Safety: Changes in concentration of blood lipids
timeFrame: 0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
measure: Safety: Changes in number of blood cells
timeFrame: 0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
measure: Safety: Changes in HbA1c (%)
timeFrame: pre-intervention baseline, post-intervention up to 24 weeks
measure: Safety: Changes in concentration of insulin
timeFrame: 0 (pre-intervention), 4, 8, 12, 16, 20, and 24 weeks (post-intervention)
measure: mTOR signaling: Change in phosphorylation of downstream targets of mTOR complex 1 and complex 2 as assessed by immunoblotting and immunoprecipitation.
timeFrame: pre-intervention baseline, post-intervention up to 24 weeks
Other outcomes:
measure: Physical Function: Change in cardiorespiratory fitness
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Physical Function: Change in maximal knee extensor muscle power
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Physical Function: Change in maximal knee extensor muscle strength
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Cognitive Function: Change in memory
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Cognitive Function: Change in learning
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Cognitive Function: Change in executive function
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Metabolic Function: Change in hepatic insulin sensitivity
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Metabolic Function: Change in glucose variability
timeFrame: 0 (pre-intervention), 12, and 24 weeks (post-intervention)
measure: Metabolic Function: Change in estimates of fasting insulin resistance
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Metabolic Function: Change in whole body insulin sensitivity.
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Metabolic Function: Change in insulin sensitivity and glucose clearance
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Change in whole blood DNA Methylated positions
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Change in skeletal muscle transcriptome
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Change in concentration of lipid species
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Change in skeletal muscle protein abundance
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
measure: Change in the concentration of metabolites
timeFrame: 0 (pre-intervention) and 24 weeks (post-intervention)
Locations:
city: Madison
country: United States
facility: University of Wisconsin-Madison
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Adam Konopka, PhD
role: PRINCIPAL_INVESTIGATOR
References: