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| ID | Type | Description | Link |
|---|---|---|---|
| 1U01AG081450-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| University of Maryland, Baltimore | OTHER |
| National Institute on Aging (NIA) | NIH |
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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| sirolimus 0.5 mg Arm | Active Comparator | Participant would receive 0.5 mg of sirolimus. |
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| sirolimus 1 mg Arm | Active Comparator | Participant would receive 1 mg of sirolimus. |
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| sirolimus 2 mg Arm | Active Comparator | Participant would receive 2 mg of sirolimus. |
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| everolimus 0.5 mg Arm | Active Comparator | Participant would receive 0.5 mg of Everolimus. |
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| everolimus 1 mg Arm | Active Comparator | Participant would receive 1 mg of Everolimus. |
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| everolimus 2 mg Arm | Active Comparator | Participant would receive 2 mg of Everolimus. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus 0.5 Mg Oral Tablet | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Cmax for Sirolimus | Maximum Sirolimus Concentration at Steady State (Cmax) | 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) | 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) | 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) | 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 | 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 | 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) | 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 | Description | Time Frame |
|---|---|---|
| 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. | Baseline, 3 months |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Irina Timofte, MD, MS | Contact | 2163347534 | Irina.Timofte@utsouthwestern.edu |
| Name | Affiliation | Role |
|---|---|---|
| Irina Timofte, MD, MS | University of Texas Southwestern Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UT Southwestern Medical Center | Recruiting | Dallas | Texas | 75390 | United States |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D013607 | Tablets |
| D000068338 | Everolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D004304 | Dosage Forms |
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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
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| Sirolimus 1Mg Oral Tablet | Drug | 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. |
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| Sirolimus 2 MG Oral Tablet | Drug | 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. |
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| Everolimus 0.5 MG Oral Tablet | Drug | 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. |
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| Everolimus 1 MG Oral Tablet | Drug | 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. |
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| Everolimus 2 MG Oral Tablet | Drug | 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. |
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| CL/F for for Everolimus | Everolimus Apparent Oral Clearance (CL/F) | 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 | 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 | 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. | 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. | 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. | 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. | 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. | Day 1 Week 1 (Baseline), Week 5, Week 9, Week 13 |
| 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. |
| 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. | 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. | 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. | 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. | Baseline, 3 months |
| D004364 |
| Pharmaceutical Preparations |