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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 26, 2022
Sponsor:
Information provided by (Responsible Party):
Sundeep Khosla, M.D., Mayo Clinic

Tracking Information
First Submitted Date  ICMJE March 17, 2020
First Posted Date  ICMJE March 18, 2020
Last Update Posted Date July 26, 2022
Actual Study Start Date  ICMJE June 9, 2020
Estimated Primary Completion Date April 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 17, 2020)
  • 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]
  • 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]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Targeting Cellular Senescence With Senolytics to Improve Skeletal Health in Older Humans
Official Title  ICMJE Targeting Cellular Senescence With Senolytics to Improve Skeletal Health in Older Humans: A Phase 2, Single-Center, 20-week, Open-Label, Randomized Controlled Trial.
Brief Summary To determine if senolytic drugs reduce senescent cell burden and reduce bone resorption markers/increase bone formation markers in elderly women.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Condition  ICMJE Healthy
Intervention  ICMJE
  • 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
  • Drug: Fisetin
    Fisetin will be supplied in 100 mg capsules to be administered orally
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: Dasatinib
    • Drug: Quercetin
  • 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
    Intervention: Drug: Fisetin
  • No Intervention: Untreated Control Group
    Subjects will not receive any intervention
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 17, 2020)
120
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2023
Estimated Primary Completion Date April 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 70 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Tammie Volkman, RN 507-538-6023 volkman.tammie@mayo.edu
Contact: Joshua Farr, PhD farr.joshua@mayo.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04313634
Other Study ID Numbers  ICMJE 18-010546
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Sundeep Khosla, M.D., Mayo Clinic
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Sundeep Khosla, M.D.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sundeep Khosla, MD Mayo Clinic
PRS Account Mayo Clinic
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP