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To determine if senolytic drugs reduce senescent cell burden and reduce bone resorption markers/increase bone formation markers in elderly women.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dasatinib plus Quercetin Treatment Goup | Experimental | Subjects will receive Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulting in five total dosing periods throughout the entire intervention |
|
| Fisetin Treatment Group | Experimental | Subjects will receive Fisetin (F; ~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulting in five total dosing periods throughout the entire intervention |
|
| Untreated Control Group | No Intervention | Subjects will not receive any intervention |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dasatinib | Drug | Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in C-terminal Telopeptide of Type I Collagen [CTX] | Percent change in serum bone turnover markers C-terminal telopeptide of type I collagen [CTX]. The C-terminal telopeptide (CTX), also known as carboxy-terminal collagen crosslinks, is a biomarker used to measure the rate of bone turnover. It provides valuable information for assessing bone health and evaluating treatment responses. | Baseline, 20 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Bone Turnover Markers | Percent change in amino-terminal propeptide of type I collagen (P1NP). The P1NP assay measures the serum concentration of the amino-terminal propeptide of type I procollagen (P1NP). As the concentration of this extension propeptide is directly proportional to the amount of new collagen laid down in bone, it can be used to assess bone formation. | Baseline, 2 weeks |
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Inclusion Criteria:
Exclusion Criteria:
Hemoglobin A1c ≥8.0% at screening
Subjects who are type II diabetic and on insulin
Abnormal screening labs: Calcium >10.1 mg/dL, Phosphorus >4.7 mg/dL, Thyroid stimulating hormone (TSH) level <0.3mU/L, Fasting blood glucose >200 mg/dL.
Presence of significant liver (total bilirubin, AST, ALT, or alkaline phosphatase >2x upper normal limit) or kidney disease (eGFR<30 ml/min/1.73 m2 (using the cystatin C blood levels for analysis). If any elevation were to be noted (2x the normal limit), the study participant would stop treatment and have levels re-drawn in a month, per the clinical judgement of the investigator
Presence of a clinical diagnosis of heart failure
Known active malignancy (including myeloma)
Current diagnosis of malabsorption or undergoing treatment for malabsorption disease
If any of the laboratory blood work drawn at the study visits return with lab values outside of the "normal limits" or show a significant change from a previous value, a repeat blood draw would be done before the subject is excluded.
Gastric bypass/reduction
Hyperthyroidism
Acromegaly
Cushing's syndrome
Hypopituitarism
Subjects with a fracture within the past six months
Undergoing treatment with any medications that affect bone turnover, including the following:
QTc >450 msec
Inability to provide consent
Inability to tolerate oral medication
Current diagnosis of hypo- or hyperparathyroidism or currently undergoing treatment for the disease
Subjects on therapeutic doses of anti-coagulants (e.g. warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc)
Subjects with hypovitaminosis D (25-hydroxyvitamin D [25(OH)D] <20 ng/ml, whose level does not improve above 20 ng/ml after two courses of 4-week treatment of 50,000 IU/d of Vitamin D. They will be referred to their primary provider should this occur.
Subjects taking anti-arrhythmic medications known to cause QTc prolongation
Subjects taking potentially senolytic agents within the last 6 months: Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax
Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy
Subjects taking H2 antagonists, unless randomized to the control group
Tyrosine kinase inhibitor therapy
Subjects not having a PBTL p16INK4a mRNA expression level >95 percentile of young female controls (this cut-off is depicted by the dotted line in Fig. 6)
Known hypersensitivity or allergy to Dasatinib orQuercetin
Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), Antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir), Rifampin
If the DXA assessment reveals a spine or femur neck T-score < -2.5, the participant will be advised of this. She would then be given the option of withdrawing from the study to immediately start an osteoporosis drug through her primary care physician or continue in the study and defer osteoporosis drug treatment for the duration of the study (20 weeks). Given that osteoporosis is a chronic, long-term disease, the 20-week deferral would pose a minimal risk to the participant and she would be free to make this choice.
Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g., cyclosporine, tacrolimus or sirolimus). If antifungals are necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic.
Subjects taking strong inhibitors of CYP3A4
Subjects on antiplatelet agents (Clopidogrel [Plavix]; Dipyridamole + Asprin [Aggrenox]; Ticagrelor [Brilinta]; Prasugrel [Effient]; Ticlopidine [Ticlid] or Other) who are unable or unwilling to reduce or hold therapy prior to and during the study drug dosing periods. Subjects may continue their previous regimen between study drug dosing periods.
Subjects on quinolone antibiotic therapy for treatment or for prevention of infections within ten days.
Subjects taking proton pump inhibitors and unwilling to discontinue therapy for two days before and during the study drug dosing periods.
Subjects with clinically evident fluid retention
Subjects with evidence of right heart strain on ECG
Subjects with a history of pulmonary hypertension
Subjects with an abnormal Complete Blood Count (clinically insignificant changes would be acceptable based on the judgement of the investigators)
Presence of any condition the Investigator believes would place the subject at risk or would preclude the subject from successfully completing all aspects of the trial.
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| Name | Affiliation | Role |
|---|---|---|
| Sundeep Khosla, MD | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic in Rochester | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39823170 | Derived | Farr JN, Monroe DG, Atkinson EJ, Froemming MN, Ruan M, LeBrasseur NK, Khosla S. Characterization of Human Senescent Cell Biomarkers for Clinical Trials. Aging Cell. 2025 May;24(5):e14489. doi: 10.1111/acel.14489. Epub 2025 Jan 17. | |
| 38956196 | Derived | Farr JN, Atkinson EJ, Achenbach SJ, Volkman TL, Tweed AJ, Vos SJ, Ruan M, Sfeir J, Drake MT, Saul D, Doolittle ML, Bancos I, Yu K, Tchkonia T, LeBrasseur NK, Kirkland JL, Monroe DG, Khosla S. Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial. Nat Med. 2024 Sep;30(9):2605-2612. doi: 10.1038/s41591-024-03096-2. Epub 2024 Jul 2. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Dasatinib Plus Quercetin Treatment Goup | Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg |
| FG001 | Fisetin Treatment Group | Subjects received Fisetin (F; ~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally |
| FG002 | Untreated Control Group | Subjects did not receive any intervention |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Dasatinib Plus Quercetin Treatment Goup | Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in C-terminal Telopeptide of Type I Collagen [CTX] | Percent change in serum bone turnover markers C-terminal telopeptide of type I collagen [CTX]. The C-terminal telopeptide (CTX), also known as carboxy-terminal collagen crosslinks, is a biomarker used to measure the rate of bone turnover. It provides valuable information for assessing bone health and evaluating treatment responses. | Posted | Median | Full Range | percent change | Baseline, 20 weeks |
|
Adverse Events were collected from baseline to end of study, approximately 20 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dasatinib Plus Quercetin Treatment Goup | Subjects received Dasatinib (D; 100 mg for two days) plus Quercetin (Q; 1000 mg total daily) for three consecutive days taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Dasatinib: Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated Quercetin: Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastric hemorrhage | Gastrointestinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal distention | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sundeep Khosla, M.D. | Mayo Clinic | 507-255-6663 | khosla.sundeep@mayo.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 8, 2023 | May 7, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000069439 | Dasatinib |
| D011794 | Quercetin |
| C017875 | fisetin |
| ID | Term |
|---|---|
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
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| Quercetin | Drug | Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg |
|
| Fisetin | Drug | Fisetin will be supplied in 100 mg capsules to be administered orally |
|
| Change in Bone Turnover Markers | Percent change in amino-terminal propeptide of type I collagen (P1NP). The P1NP assay measures the serum concentration of the amino-terminal propeptide of type I procollagen (P1NP). As the concentration of this extension propeptide is directly proportional to the amount of new collagen laid down in bone, it can be used to assess bone formation. | Baseline, 4 weeks |
| Change in Bone Turnover Markers | Percent change in amino-terminal propeptide of type I collagen (P1NP). The P1NP assay measures the serum concentration of the amino-terminal propeptide of type I procollagen (P1NP). As the concentration of this extension propeptide is directly proportional to the amount of new collagen laid down in bone, it can be used to assess bone formation. | Baseline, 20 weeks |
| Change in Bone Mineral Density (BMD) | Percent change in BMD by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, hip ((total and femoral neck (FN), and radius (total and ultra-distal)). | Baseline, 20 weeks |
| Change in Plasma Senescence-associated Secretory Phenotype (SASP) | Percent change in SASP cells (representing the total senescence cell burden) present. Assessment of senescence markers in bone at baseline and 2 weeks. | Baseline, 2 weeks |
| Protocol Violation |
|
| BG001 | Fisetin Treatment Group | Subjects received Fisetin (F; ~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally |
| BG002 | Untreated Control Group | Subjects did not receive any intervention |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Fisetin Treatment Group | Subjects received Fisetin (F; ~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally |
| OG002 | Untreated Control Group | Subjects did not receive any intervention |
|
|
|
| Secondary | Change in Bone Turnover Markers | Percent change in amino-terminal propeptide of type I collagen (P1NP). The P1NP assay measures the serum concentration of the amino-terminal propeptide of type I procollagen (P1NP). As the concentration of this extension propeptide is directly proportional to the amount of new collagen laid down in bone, it can be used to assess bone formation. | Posted | Median | Full Range | percentage change of P1NP | Baseline, 2 weeks |
|
|
|
|
| Secondary | Change in Bone Turnover Markers | Percent change in amino-terminal propeptide of type I collagen (P1NP). The P1NP assay measures the serum concentration of the amino-terminal propeptide of type I procollagen (P1NP). As the concentration of this extension propeptide is directly proportional to the amount of new collagen laid down in bone, it can be used to assess bone formation. | Outcome measure was only collected and reported for Dasatinib plus Quercetin Treatment arm and Untreated Control group arm | Posted | Median | Full Range | percentage change of P1NP | Baseline, 4 weeks |
|
|
|
|
| Secondary | Change in Bone Turnover Markers | Percent change in amino-terminal propeptide of type I collagen (P1NP). The P1NP assay measures the serum concentration of the amino-terminal propeptide of type I procollagen (P1NP). As the concentration of this extension propeptide is directly proportional to the amount of new collagen laid down in bone, it can be used to assess bone formation. | Posted | Median | Full Range | percentage change of P1NP | Baseline, 20 weeks |
|
|
|
|
| Secondary | Change in Bone Mineral Density (BMD) | Percent change in BMD by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, hip ((total and femoral neck (FN), and radius (total and ultra-distal)). | Each skeletal site was measured and assessed separately. As such, some sites (which are influenced by osteoarthritis) did not provide interpretable scans. This occurred due to motion artifacts or other issues. Therefore, the number of participants analyzed differ by skeletal site. | Posted | Median | Full Range | percentage of change in BMD | Baseline, 20 weeks |
|
|
|
| Secondary | Change in Plasma Senescence-associated Secretory Phenotype (SASP) | Percent change in SASP cells (representing the total senescence cell burden) present. Assessment of senescence markers in bone at baseline and 2 weeks. | Posted | Median | Full Range | percent change | Baseline, 2 weeks |
|
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 23 |
| 30 |
| EG001 | Fisetin Treatment Group | Subjects received Fisetin (F; ~20 mg/kg/day for three consecutive days) taken orally on an intermittent schedule (starting every 28 days) with no-therapy periods in between dosing regimens, repeated every 28 days over 20 weeks, resulted in five total dosing periods throughout the entire intervention Fisetin: Fisetin will be supplied in 100 mg capsules to be administered orally | 0 | 14 | 1 | 14 | 12 | 14 |
| EG002 | Untreated Control Group | Subjects did not receive any intervention | 0 | 30 | 0 | 30 | 5 | 30 |
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Dry Mouth | Gastrointestinal disorders | Systematic Assessment |
|
| Gastroesophageal reflux disease | Gastrointestinal disorders | Systematic Assessment |
|
| Nausea | General disorders | Systematic Assessment |
|
| Allergic rhinitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Covid | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Respiratory, thoracic and mediastinal disorders - other | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Anorexia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | Systematic Assessment |
|
| Metabolism and nutrition disorders - other | Metabolism and nutrition disorders | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Cardiac disorders - other | Cardiac disorders | Systematic Assessment |
|
| Depression | Psychiatric disorders | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Extrapyramidal disorder | Nervous system disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Muscle weakness | Nervous system disorders | Systematic Assessment |
|
| Neuralgia | Nervous system disorders | Systematic Assessment |
|
| Dry Skin | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Skin and subcutaneous tissue disorders - other | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Facial pain | General disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Flu like symptoms | General disorders | Systematic Assessment |
|
| Pain | General disorders | Systematic Assessment |
|
| Flushing | Vascular disorders | Systematic Assessment |
|
| Hot flashes | Reproductive system and breast disorders | Systematic Assessment |
|
| Menorrhagia | Reproductive system and breast disorders | Systematic Assessment |
|
| Renal and urinary disorders - other | Renal and urinary disorders | Systematic Assessment |
|
| Urinary frequency | Renal and urinary disorders | Systematic Assessment |
|
| Skin infection | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | Systematic Assessment |
|
| Cataract surgery | Eye disorders | Systematic Assessment |
|
| Fracture | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
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| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011743 | Pyrimidines |
| D044948 | Flavonols |
| D005419 | Flavonoids |
| D002867 | Chromones |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| Hip (Femoral neck ) |
|
|
| Radius |
|
|