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

Phase 2

Completed

Conditions: Healthy

Interventions: Drug: Fisetin
Drug: Dasatinib
Drug: Quercetin

Registration Number: NCT04313634

Lead Sponsor: Sundeep Khosla, M.D.

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 available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 74

Inclusion Criteria

Able and willing to provide informed consent.
Normal postmenopausal women
Aged ≥60 years

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:
- adrenocorticosteroids (> 3 months at any time or > 10 days within the previous yr, except for use of topical steroid creams or gels or inhaled steroids), anticonvulsant therapy (within the previous year), include only those taking Carbamazepine, Phenobarbital and Phenytoin,
- bisphosphonates (within the past 3 yrs),
- denosumab,
- estrogen (E) therapy or treatment with a selective E receptor modulator, or teriparatide (within the past yr)
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dasatinib plus Quercetin Treatment Goup	Quercetin	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	Fisetin	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
Dasatinib plus Quercetin Treatment Goup	Dasatinib	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

Primary Outcome Measures

Name	Time	Method
Change in C-terminal Telopeptide of Type I Collagen [CTX]	Baseline, 20 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Change in Bone Turnover Markers	Baseline, 20 weeks	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.
Change in Bone Mineral Density (BMD)	Baseline, 20 weeks	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)).
Change in Plasma Senescence-associated Secretory Phenotype (SASP)	Baseline, 2 weeks	Percent change in SASP cells (representing the total senescence cell burden) present. Assessment of senescence markers in bone at baseline and 2 weeks.