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

• ClinicalTrials.gov Identifier: NCT02874924
• Recruitment Status: Completed
• First Posted: August 22, 2016
• Results First Posted: December 4, 2018
• Last Update Posted: December 4, 2018
• Sponsor: The University of Texas Health Science Center at San Antonio
• Information provided by (Responsible Party): The University of Texas Health Science Center at San Antonio

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Locations

United States, Texas

UTHSCSA

San Antonio, Texas, United States, 78220

Sponsors and Collaborators

The University of Texas Health Science Center at San Antonio

Investigators

• 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:

Study Protocol and Statistical Analysis Plan  [PDF] November 28, 2017

More Information

• 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
• 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:

Geriatrics

Additional relevant MeSH terms:

Sirolimus; Temsirolimus; 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