Clinical trial NCT05237687: The Role of Sirolimus in Preventing Functional Decline in Older Adults
Official title: Sirolimus in Older Adults- Randomized Trial Assessing the Improvement in Phenotypic/Functional Biomarkers of Aging
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Aging
Keywords: aging
sirolimus
prevention
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
First posted: 2022-02-14
Enrollment: 10
Sex: ALL
Minimum age (years): 65
Maximum age (years): 80
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Aging is associated with progressive impairment of tissue and organ function, resulting in increased susceptibility to chronic disease, frailty and disability. Currently there are limited treatment options to alter this inevitable process. The proposed work has the potential to identify a new therapeutic intervention to decrease aging-related degenerative processes.

Rapamycin or sirolimus is a macrocyclic immunosuppressive drug that inhibits the mammalian target of rapamycin (mTOR). The mammalian target of rapamycin (mTOR) pathway is part of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway which is a fundamentally linked to cell metabolism, proliferation, differentiation, and survival. This pathway is altered in a variety of diseases, including cancers, immunosuppressed states, and fibroproliferative diseases. The mTOR kinase is considered one of the leading regulators of this pathway. Changes in mTOR signaling are closely associated with inflammation, cell growth and survival, leading to the development of chronic diseases. Recent evidence also suggests that mTOR inhibitors are promising modulators of the aging process by slowing the mechanisms of aging at the cellular level. There is a growing appreciation of the potential impact of sirolimus in slowing aging processes and in prolonging healthy lifespan.

The proposed study addresses critical gaps in our understanding of the safety and efficacy of sirolimus in delaying aging processes and is based on findings in animal studies and incidental clinical observations. The investigators will overcome potential biases with a randomized control trial. The proposed intervention study is intended to improve our insight into clinical outcomes leading to prevention of chronic diseases such as skin cancer and mortality. Our overarching hypothesis is that sirolimus is one of the first pharmacological agents that will impact the aging process and chronic disease development. Specifically, the investigators aim to investigate whether sirolimus can reduce the occurrence or increase in biomarkers of aging processes.


Eligibility criteria: Inclusion Criteria:

* Patients should be adults 65-80 years
* Women who are postmenopausal\* or status post-surgical sterilization only
* Competent to provide Informed Consent

Exclusion Criteria:

* Creatinine clearance \<30 mL/min
* Underlying chronic liver disease
* Other investigational therapy received within 1 month prior to screening visit
* Pulmonary Arterial Hypertension (PAH), mean Pulmonary Arterial Presure(mPAP)\>30 mm Hg
* Extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)
* Cardiovascular diseases, any of the following: Myocardial infarction within 6 months, planned coronary artery disease intervention , left ventricular EF \<45%

  * History of haemorrhagic central nervous system (CNS) event within 1 year from screening visit.
  * Any of the following within 3 months of screening visit :Haemoptysis or haematuria;Active gastro-intestinal (GI) bleeding or GI - ulcers; Major injury or surgery
* History of thrombotic event (including, DVT, PE, stroke and transient ischemic attack) within 1 year from screening visit.
* Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
* Planned major surgical procedures.
* Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
* Concurrent active alcohol or drug abuse.
* Clinically significant cognitive impairment
* Functional impairment (defined by ADL status)
* Patients not able to understand or follow trial procedures

Primary outcomes:
measure: Phenotypic/functional biomarkers of aging
timeFrame: 1 year
Secondary outcomes:
measure: Phenotypic/functional biomarkers of aging
timeFrame: 1 year
measure: Phenotypic/functional biomarkers of aging
timeFrame: 1 year
measure: Phenotypic/functional biomarkers of aging
timeFrame: 1 year
measure: Phenotypic/functional biomarkers of aging
timeFrame: 1 year
measure: Feasibility of collecting the laboratory biomarkers and analyzing the data regarding annual rate of decline in functional biomarkers of aging
timeFrame: 1 year
Other outcomes:
Locations:
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Irina Timofte, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest. 2013 Mar;123(3):980-9. doi: 10.1172/JCI64099. Epub 2013 Mar 1.
citation: Hsu HS, Liu CC, Lin JH, Hsu TW, Hsu JW, Su K, Hung SC. Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci Rep. 2017 Oct 27;7(1):14272. doi: 10.1038/s41598-017-14612-5.
citation: Lawrence J, Nho R. The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis. Int J Mol Sci. 2018 Mar 8;19(3):778. doi: 10.3390/ijms19030778.