Effect of mTOR Inhibition and Other Metabolism Modulating Interventions on the Elderly

NCT ID: NCT02874924

Last Updated: 2018-12-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2018-09-30

Brief Summary

The ability to mount an effective immune response declines with age, leaving the elderly increasingly susceptible to infectious diseases and cancer. Rapamycin, an FDA approved drug to prevent transplant rejection, increases the lifespan and healthspan of mice and ameliorates age-related declines in immune responsiveness, cancer survival, and cognition in laboratory animals. Investigators are conducting a translational trial to test whether rapamycin also improves life functions in humans focusing on elderly persons (aged 70-95).

Detailed Description

Inhibition of the mTOR pathway by rapamycin (RAPA), an immunosuppressive drug used as adjunct therapy in preventing solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals. Thus, it has been suggested that RAPA could be used therapeutically in humans to slow age-associated pathologies. Indeed, improvements in cognition, control of tumorigenesis, and enhancing certain aspects of immunity have been demonstrated in RAPA treated murine models. Moreover, long-term RAPA delivery in older mice is associated with changes in immune reactivity not evident in younger animals. Investigators propose to expand to a larger cohort of older humans to test the hypothesis that RAPA treatment, even in very old individuals, will result in simultaneous improvement in systems known to be negatively affected by aging. Investigators will focus on the immune system, cognition, and physical parameters of healthy aging, such as walking speed. Investigators will recruit healthy volunteers, aged 75-95 years, and randomize them to either RAPA or placebo, controlling for gender, ethnicity, and age. These groups will be used to address the following specific aims: Aim 1. Assess general parameters of immune health before and after RAPA treatment; these include serum inflammatory cytokines, PBMC subsets (naïve vs memory T cells, TREGS, etc.), and polyclonal T cell activation potential. Aim 2. Test the effects of RAPA treatment on responsiveness to a vaccine challenge; both B cell (antibody) and T cell responses will be assessed. Aim 3. Correlate immune function rejuvenation with cognitive and physical function measures in subjects treated with RAPA or placebo. Aim 4. Collect pilot data on effect of RAPA on cardiovascular function. Cognition will be assessed by three different testing tools (EXIT25, SLUMS, and TAPS). Physical performance will be measured by grip strength and 40 foot timed walks, parameters known to correlate with healthy aging. Measures of cardiovascular function (Substudy D) using MRI of the heart to evaluate diastolic function and brain MRI to analyze cerebral blood flow, with measures of pulse wave velocity and endothelial function using laser doppler flowmetry will be performed. In addition to scoring positive outcomes, investigators will assess whether there are adverse changes in clinical laboratory tests that could compromise the safe use of RAPA therapeutically in older individuals. The long-term goal is to assess whether RAPA is safe to use in an elderly population, while also being efficacious in slowing, or even reversing, the aging process.

Conditions

Aging

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

Rapamycin

Rapamycin 1mg taken once daily for 8 weeks

Group Type: EXPERIMENTAL

Rapamycin

Intervention Type: DRUG

treatment

Placebo

Placebo taken once daily for 8 weeks

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

control

Rapamycin Alone - Cardiovascular Effects

No placebo control; Rapamycin 1mg once daily for 8 weeks

Group Type: EXPERIMENTAL

Rapamycin

Intervention Type: DRUG

No placebo control in this substudy group

Interventions

Rapamycin

treatment

Intervention Type: DRUG

Placebo

control

Intervention Type: DRUG

Rapamycin

No placebo control in this substudy group

Intervention Type: DRUG

Other Intervention Names

Sirolimus; Sirolimus

Eligibility Criteria

Inclusion Criteria

• participants will be in good health with all chronic diseases (hypertension, coronary artery disease, etc.) clinically stable.
• participants must have adequate cognitive function to be able to give informed consent. This will be established by enrolling participants with CLOX 1 scores of ≥10.

Exclusion Criteria

• unstable ischemic heart disease
• clinically significant pulmonary disease
• history of immunodeficiency or receiving immunosuppressive therapy
• history of a coagulopathy or receiving a medical condition requiring anticoagulation
• an estimated glomerular filtration rate of <30ml/min
• uncontrolled hypercholesteremia >350mg/dl;
• uncontrolled hypertriglyceridemia >500mg/dl
• diabetes
• history of skin ulcers or poor wound healing
• smoking
• liver disease
• treatment with drugs known to affect cytochrome P450 3A (diltiazem, erythromycin)

• Minimum Eligible Age: 70 Years
• Maximum Eligible Age: 95 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dean Kellogg, MD PhD

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Locations

UTHSCSA

San Antonio, Texas, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

HSC20120304H

Identifier Type: -

Identifier Source: org_study_id