The Role of Sirolimus in Preventing Functional Decline in Older Adults

Aging Clinical Trial

Official title:

Sirolimus in Older Adults- Randomized Trial Assessing the Improvement in Phenotypic/Functional Biomarkers of Aging

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05237687
• Other study ID #: STU-2023-0909
• Status: Recruiting
• Phase: Phase 2
• Start date: July 2024
• Est. completion date: November 2025

Study information

• Verified date: June 2024
• Source: University of Texas Southwestern Medical Center
• Contact: Irina Timofte
• Phone: 2163347534
• Email: Irina.Timofte[@]utsouthwestern.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: November 2025
• Est. primary completion date: September 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 65 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Aging

Intervention

Drug:
• Sirolimus
Patients will be randomly assigned to sirolimus or standard of care

Locations

Country	Name	City	State
United States	UT Southwestern Medical Center	Dallas	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Irina Timofte

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phenotypic/functional biomarkers of aging	Phenotypic biomarkers of aging will be measured by SASP (senescence-associated secretory phenotype) index score at 1 year follow-up when compared to elderly patients not receiving sirolimus.	1 year
Secondary	Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging will be measured by walking speed at 1 year follow-up when compared to elderly patients not receiving sirolimus.	1 year
Secondary	Phenotypic/functional biomarkers of aging	Functional biomarkers of aging will be measured by chair stand at 1 year follow-up when compared to elderly patients not receiving sirolimus.	1 year
Secondary	Phenotypic/functional biomarkers of aging	Functional biomarkers of aging will be measured by standing balance at 1 year follow-up when compared to elderly patients not receiving sirolimus.	1 year
Secondary	Phenotypic/functional biomarkers of aging	Phenotypic/functional biomarkers of aging will be measured by body mass index at 1 year follow-up when compared to elderly patients not receiving sirolimus.	1 year
Secondary	Feasibility of collecting the laboratory biomarkers and analyzing the data regarding annual rate of decline in functional biomarkers of aging	The feasibility of collecting the laboratory biomarkers and analyzing the data regarding annual rate of decline in functional biomarkers of aging measured by walking speed, chair stand, standing balance, grip strength, body mass index, waist circumference, and muscle mass.	1 year