Clinical trial NCT06727305: MTOR Inhibitors in Older Adults
Official title: Characterization of mTOR Inhibitor Pharmacokinetics and Pharmacodynamics in Older Adults .
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Aging
Keywords: Aging
Geriatic
Disability
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: University of Maryland, Baltimore
name: National Institute on Aging (NIA)
First posted: 2024-12-10
Enrollment: 60
Sex: ALL
Minimum age (years): 65
Maximum age (years): 80
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients who will be randomized in 1:1:1:1:1:1 ratios to receive oral tablet doses of sirolimus and everolimus with concentrations of 0.5mg, 1mg, 2mg each
Primary purpose: PREVENTION

Brief summary: Over the past decades, healthcare systems face significant challenges to meet the needs of an aging population due to progressive debility, functional decline and chronic diseases development. While there is a growing appreciation of the potential impact of mTOR inhibitors on slowing aging processes, preventing chronic disease and prolonging healthy lifespan, a major challenge in developing clinical trials to establish the clinical efficacy of mTOR inhibitors is the absence of pharmacokinetics (PK) and pharmacodynamics (PD) data in older adults. The proposed study will provide the foundation for future clinical trials assessing the role of mTOR inhibitors on aging related indications

Detailed description: Study Objectives To characterize Pharmacokinetics (PK) and Pharmacodynamics (PD) of mTOR Inhibitors and determine whether mTOR Inhibitors will improve phenotypic biomarkers of aging as measured by SASP (senescence-associated secretory phenotype) index score at 3 months follow-up in older adults.

Specific Aims:

Aim 1: To characterize Pharmacokinetics (PK) and Pharmacodynamics (PD) of mTOR Inhibitors (sirolimus and everolimus) in older adults.

Aim 2: To determine whether mTOR Inhibitors will improve phenotypic biomarkers of aging as measured by SASP (senescence-associated secretory phenotype) index score at 3 months follow-up.

Exploratory Aim 3: We will also assess the feasibility of collecting the laboratory biomarkers (ESR, CRP, S6K activity, mitochondrial function, metabolomics) and data regarding the functional biomarkers of aging measured by walking speed, chair stand, standing balance, grip strength

Eligibility criteria: Inclusion Criteria:

1. Community-dwelling adults
2. Patients should be 65 Years and older
3. Patients is able to understand and follow trial procedures

Exclusion Criteria:

1. Creatinine clearance \<30 mL/min;
2. History of chronic liver disease;
3. Uncontrolled Hypertension (i.e., systolic blood pressure \>160 mm Hg);
4. Hemorrhagic central nervous system (CNS) event within 1 year from screening visit;
5. Thrombotic event (DVT,PE) within 1 year from screening visit if not on anticoagulation;
6. Planned major surgical procedures;
7. Cardiovascular diseases ( i.e., admission for heart failure or myocardial infarction within 12 months);
8. Taking medication that increase or decrease sirolimus blood concentrations;
9. Other investigational therapy received within 1 month prior to screening visit;
10. History of dementia; 11 Dependence in any Katz Basic Activities of Daily Living.

Primary outcomes:
measure: Cmax for Sirolimus
timeFrame: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
measure: Cmax for Everolimus
timeFrame: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
measure: Ctrough for Sirolimus
timeFrame: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
measure: Ctrough for Everolimus
timeFrame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
measure: AUC for Sirolimus
timeFrame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
measure: AUC for Everolimus
timeFrame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
measure: CL/F for Sirolimus
timeFrame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose
measure: CL/F for for Everolimus
timeFrame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose
measure: S6K Activity, in Sirolimus cohorts
timeFrame: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose on Day 1 and Day 14
measure: S6K Activity, in Everolimus cohorts
timeFrame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2.5, 3, 4, 6, and 12-hour post dose on Day 1 and Day 14
measure: Senescence-associated secretory phenotype (SASP) index
timeFrame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
measure: Erythrocyte sedimentation rate (ESR)
timeFrame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
measure: C-reactive protein (CRP)
timeFrame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
measure: 6-minute walk test (6MWT)
timeFrame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
measure: Short physical performance battery (SPPB)
timeFrame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13
Secondary outcomes:
measure: Change in SASP response at 3 months follow-up
timeFrame: Baseline, 3 months
measure: Change in Laboratory Biomarker response (ESR) from baseline at 3 months follow-up
timeFrame: Baseline, 3 months
measure: Change in laboratory Biomarker response (CRP) from baseline at 3 months follow-up
timeFrame: Baseline, 3 months
measure: Change in laboratory Biomarker response (S6K activity) from baseline at 3 months follow-up
timeFrame: Baseline, 3 months
measure: Change in laboratory Biomarker response (mitochondrial function) from baseline at 3 months follow-up
timeFrame: Baseline, 3 months
measure: Change in laboratory Biomarker response (metabolomics) from baseline at 3 months follow-up
timeFrame: Baseline, 3 months
Other outcomes:
Locations:
Study officials:
affiliation: UT Southwestern Medical Center
name: Irina Timofte, MD, MS
role: PRINCIPAL_INVESTIGATOR
References: