MTOR Inhibitors in Older Adults

Phase 1

Not yet recruiting

• Conditions: Aging
• Interventions: Drug: Sirolimus 0.5 Mg Oral Tablet; Drug: Sirolimus 1Mg Oral Tablet; Drug: Sirolimus 2 MG Oral Tablet; Drug: Everolimus 0.5 MG Oral Tablet; Drug: Everolimus 1 MG Oral Tablet; Drug: Everolimus 2 MG Oral Tablet

• Registration Number: NCT06727305
• Lead Sponsor: University of Texas Southwestern Medical Center

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

Study Timeline

• Study First Submitted: 2024-11-20
• Status Verified: 2024-12
• Study First Submitted QC: 2024-12-08
• Last Update Submitted: 2024-12-08
• Study First Posted: 2024-12-10
• Last Update Posted: 2024-12-10
• Study Start: 2025-05-01
• Primary Completion: 2027-09-01
• Study Completion: 2027-11-13

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 60

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
sirolimus 0.5 mg Arm	Sirolimus 0.5 Mg Oral Tablet	Participant would receive 0.5 mg of sirolimus.
sirolimus 1 mg Arm	Sirolimus 1Mg Oral Tablet	Participant would receive 1 mg of sirolimus.
sirolimus 2 mg Arm	Sirolimus 2 MG Oral Tablet	Participant would receive 2 mg of sirolimus.
everolimus 0.5 mg Arm	Everolimus 0.5 MG Oral Tablet	Participant would receive 0.5 mg of Everolimus.
everolimus 1 mg Arm	Everolimus 1 MG Oral Tablet	Participant would receive 1 mg of Everolimus.
everolimus 2 mg Arm	Everolimus 2 MG Oral Tablet	Participant would receive 2 mg of Everolimus.

Primary Outcome Measures

Name	Time	Method
Cmax for Sirolimus	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose	Maximum Sirolimus Concentration at Steady State (Cmax)
Cmax for Everolimus	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose	Maximum Everolimus Concentration at Steady State (Cmax)
Ctrough for Sirolimus	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24-hour post dose	Trough Sirolimus Concentration at Steady State (Ctrough)
Ctrough for Everolimus	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose	Trough Everolimus Concentration at Steady State (Ctrough)
AUC for Sirolimus	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	Sirolimus Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) at Steady State
AUC for Everolimus	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose	Everolimus Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) at Steady State
CL/F for Sirolimus	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	Sirolimus Apparent Oral Clearance (CL/F)
CL/F for for Everolimus	Predose (0 hour) on Day 14 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 12-hour post dose	Everolimus Apparent Oral Clearance (CL/F)
S6K Activity, in Sirolimus cohorts	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	Pharmacodynamic parameter, S6K Activity, in Sirolimus cohorts
S6K Activity, in Everolimus cohorts	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	Pharmacodynamic parameter, S6K Activity, in Everolimus cohorts
Senescence-associated secretory phenotype (SASP) index	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13	Clinical biomarker parameter (SASP) index is a clinical biomarker parameter that measures the level of proteins secreted by senescent cells in the body.
Erythrocyte sedimentation rate (ESR)	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13	Clinical biomarker parameter (ESR) is a blood test that detects and monitors inflammation in the body.
C-reactive protein (CRP)	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13	A measure of Clinical biomarker parameter (CRP), is an inflammatory marker.
6-minute walk test (6MWT)	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13	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.
Short physical performance battery (SPPB)	Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13	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.

Secondary Outcome Measures

Name	Time	Method
Change in SASP response at 3 months follow-up	Baseline, 3 months	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.
Change in Laboratory Biomarker response (ESR) from baseline at 3 months follow-up	Baseline, 3 months	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.
Change in laboratory Biomarker response (CRP) from baseline at 3 months follow-up	Baseline, 3 months	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.
Change in laboratory Biomarker response (S6K activity) from baseline at 3 months follow-up	Baseline, 3 months	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.
Change in laboratory Biomarker response (mitochondrial function) from baseline at 3 months follow-up	Baseline, 3 months	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.
Change in laboratory Biomarker response (metabolomics) from baseline at 3 months follow-up	Baseline, 3 months	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.