Exercise and Low-Dose Rapamycin in Older Adults With CAD:Cardiac Rehabilitation And Rapamycin in Elderly (CARE) Trial

Participants:

Pilot study: Patients, 60 years or older, selected for this single-center open label pilot
study will be consented for participation at initiation of CR following PCI or CABG. We will
enroll up to 18 patients; no more than 6 patients will receive a dose at one of the three
proposed levels:0.5mg, 1.0mg, and 2mg daily oral rapamycin for the duration of CR (typically
12 weeks). We will perform physical performance tests for frailty assessment, short-form 12
for quality of life, and tests for SASP [(IL-6), matrix metalloproteinase (MMP) 3, and
monocyte chemotactic protein (MCP) 1], and abdominal/thigh subcutaneous adipose biopsy for
measurement of adipocyte mitochondrial DNA copy number and to quantitate the number of
senescent preadipocytes. at baseline and at the conclusion of CR. Fasting lipid panel will
be performed at baseline and at the completion of CR. Baseline complete blood count, liver,
and kidney functions will be performed. These tests will be repeated at 14 days, 30 days, 8
weeks, and at the completion of CR. Serum rapamycin levels will be measured at 7, 14, 30
days, and at the completion of CR. The serum levels of the drug will be kept below 6ng/ml.
If the drug levels were found to be higher, next low dose of the medication will be
prescribed. Participants with serious side effects (appendix) from the medications will be
withdrawn from the study.

Patients will be enrolled in sets of three. Thirty days of monitoring must pass on all three
subjects before three more may be enrolled. The first three patients will be assigned to the
0.5 mg dose level. If two patients of those three have serious adverse events, the pilot
study will be terminated. If 1 of 3 patients has an serious adverse event, we will enroll
three more subjects at the 0.5 mg level. If those three have no serious events or if there
were no events in the first three subjects, then we will proceed to enroll three subjects at
the 1.0mg level. Otherwise, if there are 2 or more serious events in the 6 patients assigned
to 0.5mg, we will terminate the study. We will proceed similarly with the 1.0 mg level
before enrolling patients to the 2.0 mg level. If we observe 2 serious events at the 1.0 mg
level and only 3 patients have been enrolled at the 0.5mg level, we will finish the pilot by
enrolling 3 more at the 0.5 mg level. Similarly, if we observe 2 serious events at the 2.0
mg level and only have 3 subjects (with 0 events) at the 1.0 level, we will enroll 3 more at
the 1.0 level.

Randomized Trial: The Cardiac rehabilitation And Rapamycin in Elderly (CARE) study is a
prospective, randomized, phase 2 clinical trial that will be done at Mayo Clinic, Rochester,
MN. The pool of potential study participants will consist of all patients 60 years or older
with CAD who are referred to the CR following PCI or CABG. To minimize the drop out rate, we
will obtain consent at the end of first week of CR participation, since most patients who
quit CR do so in the first week. Consent will be obtained by the study coordinator.

Baseline Assessment:

Following informed consent, assessments of height, weight, and blood pressure will be made,
and all participants will have a chemistry 15 panel, complete blood cell count, and an
electrocardiogram. Race and ethnicity will be self-reported. Baseline demographic,
angiographic, and other relevant clinical and laboratory data will be entered prospectively
into a database.

Biochemical parameters: The mechanisms through which rapamycin retard cellular senescence
and extend life span are still unclear. With this aim, a better understanding of effects of
rapamycin on inflammation, mitochondrial DNA copy number, quantitation of senescent
preadipocytes and diverse biomarkers of aging could be demonstrated. To assess the effect of
CR, we will assess these parameters at baseline and then at the completion of the CR
program.

SASP: Proinflammatory biomarkers, IL-6, MMP 3 and MCP 1 will be studied (ELISA).

Patients will be randomized in a 1:1 ratio to either regular CR, or CR with the addition of
0.5mg/1.0mg/2.0mg of rapamycin. The lowest dose of rapamycin that demonstrates potential to
reduce SASP, and/or improve AAI in the pilot trial will be used.

Inclusion Criteria

1. Age 60 years or older

2. Patients eligible for CR.

3. Informed written consent.

Exclusion criteria

1. Class III or IV CHF.

2. Creatinine > 2.0 mg/dl.

3. HbA1c > 13%.

4. Any malignancy

5. Hematological disorder, including thrombocytopenia, leucopenia.

6. Noncardiac illness expected to limit survival.

7. Chronic liver disease.

8. Suspected or known pregnancy.

9. Geographically inaccessible or unable to return for follow-up.

10. Unable to understand or cooperate with protocol requirements.

12. Post organ transplant or with immune-compromised status 13. Prior stroke with
disability, severe Parkinson disease 14. Dementia 15. Post-CABG <3 months or any evidence of
active wounds or ulcers. 16.Anticipating elective surgery in the 3 months following
enrollment.

Inclusion Criteria

1. Age 60 years or older

2. Patients eligible to undergo cardiac rehabilitation.

3. Informed written consent.

Exclusion criteria

1. Class III or IV CHF.

2. Creatinine > 2.0 mg/dl.

3. HbA1c > 13%.

4. Any malignancy

5. Hematological disorder, including thrombocytopenia, leucopenia.

6. Noncardiac illness expected to limit survival.

7. Chronic liver disease.

8. Suspected or known pregnancy.

9. Geographically inaccessible or unable to return for follow-up.

10. Unable to understand or cooperate with protocol requirements.

11. Post organ transplant or with immune-compromised status

12. Prior stroke with disability, severe Parkinson disease

13. Dementia

14. Post-CABG <3 months or any evidence of active wounds or ulcers.

15. Anticipating elective surgery in the 3 months following enrollment.