The Role of Sirolimus in Preventing Functional Decline in Older Adults

• ClinicalTrials.gov Identifier: NCT05237687
• Recruitment Status: Not yet recruiting
• First Posted: February 14, 2022
• Last Update Posted: November 4, 2022
• Sponsor: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Irina Timofte, University of Texas Southwestern Medical Center

Tracking Information

• First Submitted Date: January 19, 2022
• First Posted Date: February 14, 2022
• Last Update Posted Date: November 4, 2022
• Estimated Study Start Date: December 2022
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 2, 2022)

• Phenotypic/functional biomarkers of aging [ Time Frame: 1 year ]
  Phenotypic/functional biomarkers of aging as measured by walking speed
• Phenotypic/functional biomarkers of aging [ Time Frame: 1 year ]
  Phenotypic/functional biomarkers of aging as measured by chair stand
• Phenotypic/functional biomarkers of aging [ Time Frame: 1 year ]
  Phenotypic/functional biomarkers of aging as measured by standing balance
• Phenotypic/functional biomarkers of aging [ Time Frame: 1 year ]
  Phenotypic/functional biomarkers of aging as measured by grip strength
• Phenotypic/functional biomarkers of aging [ Time Frame: 1 year ]
  Phenotypic/functional biomarkers of aging as measured by body mass index
• Phenotypic/functional biomarkers of aging [ Time Frame: 1 year ]
  Phenotypic/functional biomarkers of aging as measured by muscle mass
• Phenotypic/functional biomarkers of aging [ Time Frame: 1 year ]
  Phenotypic/functional biomarkers of aging as measured by waist circumference

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 2, 2022)

• Circulating biomarkers of aging as measured by ESR [ Time Frame: 1 year ]
  We are going to check circulating biomarkers of aging as measured by erythrocyte sedimentation rate(ESR)
• Circulating biomarkers of aging as measured by C-reactive protein(CRP) [ Time Frame: 1 year ]
  We are going to check circulating biomarkers of aging as measured by C-reactive protein(CRP)
• Circulating biomarkers of aging as measured by levels of Hemoglobin(Hb) [ Time Frame: 1 year ]
  We are going to check circulating biomarkers of aging as measured by levels of Hemoglobin(Hb)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Role of Sirolimus in Preventing Functional Decline in Older Adults
• Official Title: The Role of Sirolimus in Preventing Functional Decline in Older Adults

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Aging

Intervention

Drug: Sirolimus

Patients will be randomly assigned to sirolimus or standard of care

Study Arms

• Active Comparator: Intervention
  Patients randomized to the intervention will initially take 0.5 mg sirolimus. The dose will be adjusted weekly to obtain a sirolimus levels of 5-7 ng/ml whole blood in the first months. After the first month, the patient will have monthly blood work and will be followed in clinic every 3 months. Functional assessment and aging biomarkers will be obtained at baseline and 1 year follow up. Completion of the 1-year treatment period will be followed by a follow-up visit 4 weeks later.
  Intervention: Drug: Sirolimus
• No Intervention: Control
  Interventions: standard of care Patients are not going to receive any additional intervention.

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: February 2, 2022): 14
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2025
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• patients 55 years or older

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Irina Timofte; 2163347534; Irina.Timofte@utsouthwestern.edu

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT05237687
• Other Study ID Numbers: STU-2022-0060
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Irina Timofte, University of Texas Southwestern Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Texas Southwestern Medical Center
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: University of Texas Southwestern Medical Center
• Verification Date: October 2022