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Targeting Cellular Senescence With Senolytics to Improve Skeletal Health in Older Humans

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ClinicalTrials.gov Identifier: NCT04313634
Recruitment Status : Recruiting
First Posted : March 18, 2020
Last Update Posted : July 21, 2021
Sponsor:
Information provided by (Responsible Party):
Sundeep Khosla, M.D., Mayo Clinic

Brief Summary:
To determine if senolytic drugs reduce senescent cell burden and reduce bone resorption markers/increase bone formation markers in elderly women.

Condition or disease Intervention/treatment Phase
Healthy Drug: Dasatinib Drug: Quercetin Drug: Fisetin Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: Targeting Cellular Senescence With Senolytics to Improve Skeletal Health in Older Humans: A Phase 2, Single-Center, 20-week, Open-Label, Randomized Controlled Trial.
Actual Study Start Date : June 9, 2020
Estimated Primary Completion Date : April 30, 2022
Estimated Study Completion Date : March 31, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dasatinib plus Quercetin Treatment Goup
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
Drug: Dasatinib
Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated
Other Name: Sprycel

Drug: Quercetin
Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg

Experimental: Fisetin Treatment Group
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
Drug: Fisetin
Fisetin will be supplied in 100 mg capsules to be administered orally

No Intervention: Untreated Control Group
Subjects will not receive any intervention



Primary Outcome Measures :
  1. Percent Changes in C-terminal telopeptide of type I collagen [CTX] [ Time Frame: Baseline, 20 weeks ]
    Percent changes in serum bone turnover markers C-terminal telopeptide of type I collagen [CTX]

  2. Percent Changes in amino-terminal propeptide of type I collagen [P1NP] [ Time Frame: Baseline, 20 weeks ]
    Percent changes in serum bone turnover markers amino-terminal propeptide of type I collagen [P1NP]



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Ages Eligible for Study:   70 Years and older   (Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Able and willing to provide informed consent.
  • Normal postmenopausal women
  • Aged ≥70 years

Exclusion Criteria:

  • Hemoglobin A1c ≥8.0%
  • Abnormal screening labs (see below)
  • Presence of significant liver or kidney disease
  • Presence of heart failure
  • Malignancy (including myeloma)
  • Malabsorption, including gastric bypass / reduction, Crohn's disease
  • Subjects who are diabetic and on insulin, sulfonylureas or SGLT2 inhibitors. Diabetes alone or Metformin use are not grounds for exclusion.
  • 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:

    • adrenocorticosteroids (> 3 months at any time or > 10 days within the previous yr), anticonvulsant therapy (within the previous year),
    • calcium supplementation of > 1200 mg/d (within the preceding 3 months),
    • bisphosphonates (within the past 3 yrs),
    • denosumab,
    • estrogen (E) therapy or treatment with a selective E receptor modulator, or teriparatide (within the past yr)
    • β-blockers
  • QTc >450 msec
  • Inability to provide consent
  • Inability to tolerate oral medication
  • eGFR<30 ml/min/1.73 m2
  • 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 8-week treatment of 1000 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: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax
  • Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy
  • Subjects taking H2 antagonists
  • 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, Quercetin, or Fisetin
  • Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), Antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir), Rifampin
  • Subjects taking the following other drugs if they cannot be held for at least 2 days before and during administration of Fisetin: digoxin, lithium, all statins, repaglidine, bosentan, gemfibrozil, olmesartan, enalapril, valsartan, methotrexate, corticosteroids, eluxadoline, eltrombopag, nitroglycerin, pioglitazone, glyburide, enzalutamide, ezetimibe, colchicine, imatinib, cyclosporine, tacolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, heparin, full dose ASA, clopidogrel, celecoxib, desipramine, thioridazine, venlafaxine, tizanidine, atomoxetine, voriconazole, citalopram, diazepam, escitalopram, propranolol, clozapine, cyclobenzaprine, mexiletine, olanzapine, ondansetron, riluzole,
  • 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 absolutely 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04313634


Contacts
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Contact: Tammie Volkman, RN 507-538-6023 volkman.tammie@mayo.edu
Contact: Joshua Farr, PhD farr.joshua@mayo.edu

Locations
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United States, Minnesota
Mayo Clinic in Rochester Recruiting
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Sundeep Khosla, M.D.
Investigators
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Principal Investigator: Sundeep Khosla, MD Mayo Clinic
Additional Information:
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Responsible Party: Sundeep Khosla, M.D., Principal Investigator, Mayo Clinic
ClinicalTrials.gov Identifier: NCT04313634    
Other Study ID Numbers: 18-010546
First Posted: March 18, 2020    Key Record Dates
Last Update Posted: July 21, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Dasatinib
Quercetin
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antioxidants
Protective Agents
Physiological Effects of Drugs