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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02874924
Recruitment Status : Completed
First Posted : August 22, 2016
Results First Posted : December 4, 2018
Last Update Posted : December 4, 2018
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio

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).

Condition or disease Intervention/treatment Phase
Aging Drug: Rapamycin Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Effect of Mammalian Target of Rapamycin Inhibition and Other Metabolism Modulating Interventions on the Elderly: Immune, Cognitive, and Functional Consequences
Study Start Date : June 2016
Actual Primary Completion Date : September 2018
Actual Study Completion Date : September 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Rapamycin
Rapamycin 1mg taken once daily for 8 weeks
Drug: Rapamycin
Other Name: Sirolimus

Placebo Comparator: Placebo
Placebo taken once daily for 8 weeks
Drug: Placebo

Experimental: Rapamycin Alone - Cardiovascular Effects
No placebo control; Rapamycin 1mg once daily for 8 weeks
Drug: Rapamycin
No placebo control in this substudy group
Other Name: Sirolimus

Primary Outcome Measures :
  1. Immunological Responses [ Time Frame: 8 weeks ]
    T cell function measured by number of T cells per millimeter cubed.

Secondary Outcome Measures :
  1. Physical Performance [ Time Frame: 8 weeks ]
    walking speed: Timed 40-foot walk: each participant will perform 3 walks (timed with a stopwatch) at their preferred walking speed over a measured 40-foot path. Results will be averaged for analysis. The faster the walking speed the better the performance.

  2. Cognitive Function [ Time Frame: 8 weeks ]

    The Executive Interview (EXIT25) - This test is a brief bedside test that consists of 25 items measuring abilities that include:

    Executive functioning, Motor sequencing, Spoken alternate sequencing, Verbal fluency, Design fluency, Persistence, Resistance to interference, Reflexes Scoring directions are listed under each of the 25 portions of this test. For each section, the client is given a score of a 0, 1, or 2. A score "0" indicates no impairment, a score of "1" indicates some impairment, and a score of "2" indicates severe impairment. Directions for what qualifies as each score are listed under each section. The points are totaled and criteria are given for severe, moderate, and no impairment. Minimum score is -0- and maximum is 50. A score of 15 or below indicates normal executive functioning, a score of above 15 indicates moderate to severe impairment.

Other Outcome Measures:
  1. Cardiovascular Effect [ Time Frame: 8 weeks ]
    Pulse Wave Velocity is measured using an Electrocardiogram (ECG)

  2. Volume of Diastolic Filling [ Time Frame: 8 weeks ]
    Diastolic function was assessed using Magnetic Resonance Imaging (MRI) of the heart to measure the diastolic filling of the heart in participants in the open label rapamycin group.

Information from the National Library of Medicine

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Ages Eligible for Study:   70 Years to 95 Years   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria: age 70-95

  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02874924

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United States, Texas
San Antonio, Texas, United States, 78220
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
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Principal Investigator: Dean Kellogg, MD PhD University of Texas
  Study Documents (Full-Text)

Documents provided by The University of Texas Health Science Center at San Antonio:
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Responsible Party: The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT02874924    
Other Study ID Numbers: HSC20120304H
First Posted: August 22, 2016    Key Record Dates
Results First Posted: December 4, 2018
Last Update Posted: December 4, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by The University of Texas Health Science Center at San Antonio:
Additional relevant MeSH terms:
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MTOR Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action