MTOR Inhibitors in Older Adults

Phase 2RecruitingNCT06727305

University of Texas Southwestern Medical Center60 enrolled

Overview

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

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

Conditions

Interventions

Sirolimus 0.5 Mg Oral TabletDRUG

Sirolimus 0.5 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.

Sirolimus 1Mg Oral TabletDRUG

Sirolimus 1 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.

Sirolimus 2 MG Oral TabletDRUG

Sirolimus 2 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.

Everolimus 0.5 MG Oral TabletDRUG

Everolimus 0.5 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.

Everolimus 1 MG Oral TabletDRUG

Everolimus 1 mg oral tablets daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.

Everolimus 2 MG Oral TabletDRUG

Everolimus 2 mg oral tablets for daily for 2 weeks and complete PK/PD testing. After the first 2 weeks, dose increase, or dose reduction will be made to obtain a stable blood level of 5-7 ng/ml.

Eligibility

Sex: ALLMin age: 65 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (1)

UT Southwestern Medical Center

Dallas, Texas, United States

RECRUITING

Outcomes

Primary Outcomes

Cmax for Sirolimus

Maximum Sirolimus Concentration at Steady State (Cmax)

Time frame: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose

Cmax for Everolimus

Maximum Everolimus Concentration at Steady State (Cmax)

Time frame: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose

Ctrough for Sirolimus

Trough Sirolimus Concentration at Steady State (Ctrough)

Time frame: Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose

Ctrough for Everolimus

Trough Everolimus Concentration at Steady State (Ctrough)

Time frame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose

AUC for Sirolimus

Sirolimus Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) at Steady State

Time frame: 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

AUC for Everolimus

Everolimus Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) at Steady State

Time frame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose

CL/F for Sirolimus

Sirolimus Apparent Oral Clearance (CL/F)

Time frame: 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

CL/F for for Everolimus

Everolimus Apparent Oral Clearance (CL/F)

Time frame: Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose

S6K Activity, in Sirolimus cohorts

Pharmacodynamic parameter, S6K Activity, in Sirolimus cohorts

Time frame: 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

S6K Activity, in Everolimus cohorts

Pharmacodynamic parameter, S6K Activity, in Everolimus cohorts

Time frame: 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

Senescence-associated secretory phenotype (SASP) index

Clinical biomarker parameter (SASP) index is a clinical biomarker parameter that measures the level of proteins secreted by senescent cells in the body.

Time frame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13

Erythrocyte sedimentation rate (ESR)

Clinical biomarker parameter (ESR) is a blood test that detects and monitors inflammation in the body.

Time frame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13

C-reactive protein (CRP)

A measure of Clinical biomarker parameter (CRP), is an inflammatory marker.

Time frame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13

6-minute walk test (6MWT)

The 6MWT is simply a record of the distance (in meters) traveled by a given patient at his or her self-selected walking speed over a period of six minutes.

Time frame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13

Short physical performance battery (SPPB)

Clinical biomarker parameter (SPPB) assesses lower extremity function in older adults. The test battery consists of three physical tasks (walking, sit-to-stand and balance) to assess functional mobility. The test will be performed according to standardized procedure. The maximal total score is 12 and higher total scores indicate a better lower extremity functioning.

Time frame: Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13

Secondary Outcomes

Change in SASP response at 3 months follow-up

SASP (senescence-associated secretory phenotype) index score is quantified using blood work comparing results at baseline and at 3 months follow-up. Patients with high SASP scores have a poor survival rate, while patients with low SASP scores have a good survival rate.

Time frame: Baseline, 3 months

Change in Laboratory Biomarker response (ESR) from baseline at 3 months follow-up

Feasibility of collecting the laboratory biomarker - Erythrocyte sedimentation rate (ESR) is assessed by change in blood work readings ((millimeters per hour \[mm/hour\])) at 3 months follow-up.

Time frame: Baseline, 3 months

Change in laboratory Biomarker response (CRP) from baseline at 3 months follow-up

Feasibility of collecting the laboratory biomarker- C-Reactive Protein (CRP) is assessed by change in blood work readings (mg/dl) at 3 months follow-up.

Time frame: Baseline, 3 months

Change in laboratory Biomarker response (S6K activity) from baseline at 3 months follow-up

Feasibility of collecting the laboratory biomarker- S6 Kinase (S6K) activity is assessed by change in blood work readings (mg/dl) at 3 months follow-up.

Time frame: Baseline, 3 months

Change in laboratory Biomarker response (mitochondrial function) from baseline at 3 months follow-up

Feasibility of collecting the laboratory biomarker (mitochondrial function) is assessed by change in blood work readings at 3 months follow-up. The mitochondrial function will be measured through the Bioenergetic Health Index. The Bioenergetic Health Index (BHI) is calculated using the following formula: BHI=(ATP-linked×reserve capacity)/(proton leak×non-mitochondrial) - as described by Chacko et al. The expected range is 0-100.

Time frame: Baseline, 3 months

Change in laboratory Biomarker response (metabolomics) from baseline at 3 months follow-up

Feasibility of collecting the laboratory biomarker (metabolomics) is assessed by change in blood work readings at 3 months follow-up. Changes in blood metabolomics are quantified by measuring the concentration levels of individual metabolites within a blood sample using techniques like mass spectrometry (MS) or nuclear magnetic resonance (NMR) spectroscopy, where the relative abundance of each metabolite is compared between different samples, allowing for identification of changes in metabolic pathways based on variations in metabolite levels. The unit of measure is "concentration", usually expressed in micromolar (µM) or millimolar (mM), as it represents the quantity of a specific metabolite per unit volume of the sample.

Central Contacts

Irina Timofte, MD, MS

CONTACT

2163347534 Irina.Timofte@utsouthwestern.edu

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Time frame: Baseline, 3 months