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

• ClinicalTrials.gov Identifier: NCT04313634
• Recruitment Status: Active, not recruiting
• First Posted: March 18, 2020
• Last Update Posted: March 27, 2024
• Sponsor: Sundeep Khosla, M.D.
• Information provided by (Responsible Party): Sundeep Khosla, M.D., Mayo Clinic

Tracking Information

• First Submitted Date: March 17, 2020
• First Posted Date: March 18, 2020
• Last Update Posted Date: March 27, 2024
• Actual Study Start Date: June 9, 2020
• Actual Primary Completion Date: June 6, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 21, 2023)

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]

Original Primary Outcome Measures (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]

Current Secondary Outcome Measures (submitted: March 25, 2024)

• Percent changes in bone turnover markers [ Time Frame: Baseline, 4, 8, 12, 16, 20 weeks ]
  Percent Changes in amino-terminal propeptide of type I collagen [P1NP] and CTX
• BMD changes [ Time Frame: Baseline, 20 weeks ]
  Bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) at the lumbar spine, hip (total and femoral neck [FN]), and radius (total and ultra-distal).
• Plasma SASP factors [ Time Frame: Baseline, 4, 8, 12, 16, 20 weeks ]
  Plasma SASP factors

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Targeting Cellular Senescence With Senolytics to Improve Skeletal Health in Older Humans
• 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.
• 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Supportive Care
• Condition: Healthy

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
• Drug: Fisetin
  Fisetin will be supplied in 100 mg capsules to be administered orally

Study Arms

• 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

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: March 17, 2020): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 6, 2024
• Actual Primary Completion Date: June 6, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 60 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04313634
• Other Study ID Numbers: 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

• Plan to Share IPD: No

• Current Responsible Party: Sundeep Khosla, M.D., Mayo Clinic
• Original Responsible Party: Same as current
• Current Study Sponsor: Sundeep Khosla, M.D.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sundeep Khosla, MD; Mayo Clinic

• PRS Account: Mayo Clinic
• Verification Date: March 2024