Healthy
Conditions
Brief summary
To determine if senolytic drugs reduce senescent cell burden and reduce bone resorption markers/increase bone formation markers in elderly women.
Interventions
DRUGDasatinib
Dasatinib will be supplied as 100 mg tablet white to off-white, biconvex, oval, film- coated
DRUGQuercetin
Quercetin will be supplied as quercetin phytosome (sophora japonica concentrate (leaf) / phosphatidylcholine complex from Sunflower) 250 mg
DRUGFisetin
Fisetin will be supplied in 100 mg capsules to be administered orally
Sponsors
Sundeep Khosla, M.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
60 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Bone Turnover Markers | Baseline, 2 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 30 |
| 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 | 14 |
| Untreated Control Group Subjects did not receive any intervention | 30 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Dasatinib Plus Quercetin Treatment Goup | Total | Untreated Control Group | Fisetin Treatment Group |
|---|---|---|---|---|
| Age, Continuous | 71.2 years STANDARD_DEVIATION 4.9 | 73.7 years STANDARD_DEVIATION 5.7 | 74.4 years STANDARD_DEVIATION 6.7 | 75.9 years STANDARD_DEVIATION 3.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 74 Participants | 30 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 73 Participants | 30 Participants | 14 Participants |
| Region of Enrollment United States | 30 participants | 74 participants | 30 participants | 14 participants |
| Sex: Female, Male Female | 30 Participants | 74 Participants | 30 Participants | 14 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 14 | 0 / 30 |
| other Total, other adverse events | 23 / 30 | 12 / 14 | 5 / 30 |
| serious Total, serious adverse events | 0 / 30 | 1 / 14 | 0 / 30 |
Outcome results
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.
Time frame: Baseline, 20 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib Plus Quercetin Treatment Goup | Change in C-terminal Telopeptide of Type I Collagen [CTX] | -4.1 percent change |
| Fisetin Treatment Group | Change in C-terminal Telopeptide of Type I Collagen [CTX] | 13.7 percent change |
| Untreated Control Group | Change in C-terminal Telopeptide of Type I Collagen [CTX] | -7.7 percent change |
p-value: 0.611Wilcoxon (Mann-Whitney)
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)).
Time frame: Baseline, 20 weeks
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dasatinib Plus Quercetin Treatment Goup | Change in Bone Mineral Density (BMD) | Radius | 0.4 percentage of change in BMD |
| Dasatinib Plus Quercetin Treatment Goup | Change in Bone Mineral Density (BMD) | Hip (Femoral neck ) | -0.3 percentage of change in BMD |
| Dasatinib Plus Quercetin Treatment Goup | Change in Bone Mineral Density (BMD) | Lumbar Spine | -0.2 percentage of change in BMD |
| Fisetin Treatment Group | Change in Bone Mineral Density (BMD) | Hip (Femoral neck ) | -0.9 percentage of change in BMD |
| Fisetin Treatment Group | Change in Bone Mineral Density (BMD) | Lumbar Spine | 0 percentage of change in BMD |
| Fisetin Treatment Group | Change in Bone Mineral Density (BMD) | Radius | 0.7 percentage of change in BMD |
| Untreated Control Group | Change in Bone Mineral Density (BMD) | Lumbar Spine | 0.5 percentage of change in BMD |
| Untreated Control Group | Change in Bone Mineral Density (BMD) | Radius | 0.2 percentage of change in BMD |
| Untreated Control Group | Change in Bone Mineral Density (BMD) | Hip (Femoral neck ) | -0.5 percentage of change in BMD |
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.
Time frame: Baseline, 2 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib Plus Quercetin Treatment Goup | Change in Bone Turnover Markers | 0.8 percentage change of P1NP |
| Fisetin Treatment Group | Change in Bone Turnover Markers | -31.9 percentage change of P1NP |
| Untreated Control Group | Change in Bone Turnover Markers | -15.2 percentage change of P1NP |
p-value: 0.02Wilcoxon (Mann-Whitney)
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.
Time frame: Baseline, 4 weeks
Population: Outcome measure was only collected and reported for Dasatinib plus Quercetin Treatment arm and Untreated Control group arm
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib Plus Quercetin Treatment Goup | Change in Bone Turnover Markers | 4.2 percentage change of P1NP |
| Fisetin Treatment Group | Change in Bone Turnover Markers | -12.1 percentage change of P1NP |
p-value: 0.024Wilcoxon (Mann-Whitney)
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.
Time frame: Baseline, 20 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib Plus Quercetin Treatment Goup | Change in Bone Turnover Markers | -8.6 percentage change of P1NP |
| Fisetin Treatment Group | Change in Bone Turnover Markers | 4.5 percentage change of P1NP |
| Untreated Control Group | Change in Bone Turnover Markers | 0.1 percentage change of P1NP |
p-value: 0.149Wilcoxon (Mann-Whitney)
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.
Time frame: Baseline, 2 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib Plus Quercetin Treatment Goup | Change in Plasma Senescence-associated Secretory Phenotype (SASP) | -2.6 percent change |
| Fisetin Treatment Group | Change in Plasma Senescence-associated Secretory Phenotype (SASP) | -0.9 percent change |
| Untreated Control Group | Change in Plasma Senescence-associated Secretory Phenotype (SASP) | -2.5 percent change |
p-value: 0.953Wilcoxon (Mann-Whitney)