A Phase 2 interventional study of Rapamycin and Placebo in Aging, sponsored by The University of Texas Health Science Center at San Antonio. Completed at 1 site in United States. Open to participants aged 70 Years to 95 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-12-04.
Sponsored by The University of Texas Health Science Center at San Antonio · Phase 2, Interventional, and Basic science
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).
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.
The University of Texas Health Science Center at San Antonio is the lead sponsor of 435 studies on the registry; 88 are open to participants now.
Of its 62 completed or terminated interventional studies of FDA-regulated products, 31 (50%) have results posted.
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Inclusion Criteria: age 70-95
Exclusion Criteria:
Rapamycin 1mg taken once daily for 8 weeks
Drug: Rapamycin
Placebo taken once daily for 8 weeks
Drug: Placebo
No placebo control; Rapamycin 1mg once daily for 8 weeks
Drug: Rapamycin
treatment
Also known as: Sirolimus
control
No placebo control in this substudy group
Also known as: Sirolimus
Immunological Responses
T cell function measured by number of T cells per millimeter cubed.
Time frame: 8 weeks
Physical Performance
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.
Time frame: 8 weeks
Cognitive Function
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.
Time frame: 8 weeks
Cardiovascular Effect
Pulse Wave Velocity is measured using an Electrocardiogram (ECG)
Time frame: 8 weeks
Volume of Diastolic Filling
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.
Time frame: 8 weeks
| Milestone | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects |
|---|---|---|---|
| Started | 14 | 14 | 6 |
| Completed | 11 | 14 | 6 |
| Not completed | 3 | 0 | 0 |
| Withdrew: Adverse event | 2 | 0 | 0 |
| Withdrew: Withdrawal by subject | 1 | 0 | 0 |
T cell function measured by number of T cells per millimeter cubed.
| cells/mm^3 | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects |
|---|---|---|---|
| Immunological Responses | 8.33 ± 3.82 | 11.24 ± 4.45 | — |
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.
| Seconds | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects |
|---|---|---|---|
| Physical Performance | 7.75 ± 1.12 | 7.17 ± 1.12 | — |
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.
| score on a scale | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects |
|---|---|---|---|
| Cognitive Function | 7.2 ± 4.52 | 6.92 ± 4.23 | — |
Pulse Wave Velocity is measured using an Electrocardiogram (ECG)
No measurements were reported for this outcome.
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.
| milliliters | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects |
|---|---|---|---|
| Volume of Diastolic Filling | — | — | 132.84 ± 26.82 |
Collected over 8 weeks per subject. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Rapamycin | 0/14 (0%) | 0/14 (0%) | 2/14 (14.3%) |
| Placebo | 0/14 (0%) | 0/14 (0%) | 0/14 (0%) |
| Rapamycin Alone - Cardiovascular Effects | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) |
| Event | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects |
|---|---|---|---|
| Rash of faceGeneral disorders | 1/14 | 0/14 | 0/6 |
| DiarrheaGastrointestinal disorders | 1/14 | 0/14 | 0/6 |
| Age, Customized(Participants) | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects | Total |
|---|---|---|---|---|
| Age, 70 years and older | 14 | 14 | 6 | 34 |
| Sex: Female, Male(Participants) | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects | Total |
|---|---|---|---|---|
| Female | 5 | 5 | 0 | 10 |
| Male | 9 | 9 | 6 | 24 |
| Ethnicity (NIH/OMB)(Participants) | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects | Total |
|---|---|---|---|---|
| Hispanic or Latino | 7 | 2 | 1 | 10 |
| Not Hispanic or Latino | 7 | 12 | 5 | 24 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 0 |
| White | 14 | 14 | 6 | 34 |
| More than one race | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Region of Enrollment(Participants) | Rapamycin | Placebo | Rapamycin Alone - Cardiovascular Effects | Total |
|---|---|---|---|---|
| United States | 14 | 14 | 6 | 34 |
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The University of Texas Health Science Center at San Antonio