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

• Status: Recruiting
• Trial end date: 2023-03-31
• Target enrollment: 0
• Participant gender: Female

Summary

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

• Phase: Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Sundeep Khosla, M.D.
• Treatments: Dasatinib; Quercetin

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.