This is a prospective, randomized, double-blind, active control clinical trial to evaluate the safety and efficacy of a senolytic agent (Fisetin) and an anti-fibrotic agent (Losartan), used independently and in combination, to improve beneficial effect demonstrated by the active control which is to be injection of autologous bone marrow aspirate concentrate (BMAC) into an osteoarthritic knee.

This is a prospective, randomized, double-blind, active control clinical trial to evaluate the safety and efficacy of a senolytic agent (Fisetin) and an anti-fibrotic agent (Losartan), used independently and in combination, to improve beneficial effect demonstrated by the active control which is to be injection of autologous bone marrow aspirate concentrate (BMAC) into an osteoarthritic knee. 100 subjects with symptomatic unilateral or bilateral knee osteoarthritis (Kellgren-Lawrence grade II-IV) will be randomized into one of four arms (1:1:1:1). All subjects will receive an injection of BMAC. Group 1-n=25: Control (BMA concentrate + Fisetin Placebo + Losartan Placebo) Group 2-n=25: BMA concentrate + Fisetin Placebo + Active Losartan Group 3-n=25: BMA concentrate + Active Fisetin + Losartan Placebo Group 4-n=25: BMA concentrate + Active Fisetin + Active Losartan

Inclusion Criteria:

1. Capacity to personally give informed consent (consent via legally authorized representative will not be accepted) and who are willing to comply with all study-related procedures and assessments;
2. Between 40 and 85 years of age;
3. Ambulatory persons with osteoarthritis (OA) of at least one knee (Kellgren-Lawrence grade II-IV);
4. Baseline pain of 3-10 points on the target knee and a pain differential of at least -2 points on the contralateral knee as exhibited by the worst pain score (on the 11-point Numeric Rating Scale) for the previous week.

Exclusion Criteria:

Previous or Planned Knee Surgeries, Procedures and/or Treatments:

1. Planned surgery on either the contralateral or target knee at any time during the Study period including dosing and follow-up;

2. Within 6 months of signing informed consent has received diagnostic arthroscopy of the target knee or arthroscopic surgery (including microfracture and meniscectomy) on the target knee;

3. Within 12 weeks of signing informed consent has received intra-articular treatment of the target knee with steroids or hyaluronic acid derivatives;

4. History of previous total or partial arthroplasty in the target knee. Partial or total arthroplasty in the contralateral knee is acceptable as long as the surgery was performed at least 6 months prior to enrollment and the operative knee is asymptomatic;

   Current and/or Previous Medical Conditions, Surgeries and/or Procedures:

5. Within 2 years of signing informed consent history of active blood disorders (i.e., DVTs, chronic blood clotting, hemophilia, leukemia, myeloma, etc.); or active malignancy of any type or history of a malignancy (with the exception of subjects with a history of treated basal or squamous cell carcinoma);

6. Current diagnosis of fibromyalgia based on ACR criteria;

7. History of diabetes mellitus according to the American Diabetes Association criteria, or subjects previously diagnosed by a qualified physician as having diabetes (American Diabetes Association Standards of Medical Care in Diabetes 2016);

8. Any active known or suspected systemic autoimmune disease (except for vitiligo, residual auto-immune hypothyroidism requiring hormone replacement only, psoriasis not requiring systemic treatment for two years, conditions not expected to recur in the absence of an external trigger) or any history of a systemic inflammatory arthritis such as psoriatic, rheumatoid, ankylosing spondylitis or reactive arthritis;

9. Within 6 months of signing informed consent has undergone regenerative knee joint procedures including, but not limited to, platelet-rich plasma injections, mesenchymal stem cell transplantation, autologous chondrocyte transplantation, or mosaicplasty;

10. Current or prior history of other joint diseases including but not limited to joint dysplasia, crystal-induced arthropathy (such as gout, or calcium pyrophosphate deposition disease evidenced by clinical and/or radiographic means), aseptic osteonecrosis, acromegaly, Paget's disease, Ehlers-Danlos Syndrome, Gaucher's disease, Stickler syndrome, joint infection, hemochromatosis, or neuropathic arthropathy of any cause;

11. Any medical condition, including findings in laboratory or medical history or in the baseline assessments, that (in the opinion of the Principal Investigator or his designee), constitutes a risk or contraindication for participation in the Study or that could interfere with the Study conduct, endpoint evaluation or prevent the subject from fully participating in all aspects of the Study;

12. Females who nursing a child, are pregnant or planning to become pregnant during study drug dosing;

13. Males who do not wish to abstain from sex with women of childbearing potential without use of contraceptive protection by either party during study drug dosing;

14. Unable to safely undergo an MRI based on MRI safety screening (for example, due to incompatible device/implant, severe claustrophobia, BMI greater than 40 kg/m2, or size exceeding the limits of the of the MRI equipment (coil and gantry);

    Current and/or Previous Medications and Supplements:

15. Taking medications that affect insulin activity, including Metformin or Acarbose within 1 week of signing informed consent;

16. Currently taking Losartan or Fisetin, allergy to any active or inactive ingredient of Losartan or Fisetin, and/or currently taking medication with known Losartan or Fisetin interaction;

17. Within 3 months of signing informed consent have taken senolytic agents including: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax;

18. Subjects with any of the following drug/medication statuses:

    1. Currently taking Losartan;
    2. Currently taking Warfarin or related anticoagulants;
    3. Currently taking Lithium;
    4. Opioid analgesics taken in the past 8 weeks and are not willing to discontinue these medications through the duration of the study;
    5. Senolytic agents taken within the past 3 months and are not willing to discontinue these medications through the duration of the study, including: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax;
    6. Drugs that induce significant cellular stress and are not willing to discontinue these medications through the duration of the study, including alkylating agents, anthracyclines, platins, other chemotherapy drugs;
    7. Subjects taking the following other drugs if they cannot be held (per the Principal Investigator) for at least 2 days before and during administration of Fisetin:

    cyclosporine, tacrolimus, repaglinide, and bosentan.

19. Taking a glucocorticoid within 1 month of signing informed consent;

20. Within 8 weeks of signing informed consent has used opioid analgesics, and are not willing to discontinue these medications through the duration of the study;

21. Within the 3 months of signing informed consent has received anticonvulsant therapy, pharmacological doses of thyroid hormone (causing decline of thyroid stimulating hormone below normal), calcium supplementation of > 1200 mg/d;

22. Within the 12 months prior to signing informed consent received any medications that affect bone turnover, including: adrenocorticosteroids (> 3 months at any time or > 10 days, estrogen (E) therapy or treatment with a selective E receptor modulator, or teriparatide;

23. Inability to tolerate oral medication;

24. Inadequate amount of BMA collected to serve the needs of the patient, ProofPoint Biologics and/or of the SPRI laboratory.

Behavioral Modification - Participants will be educated about the risk of excessive caffeine usage. Participants will be encouraged to reduce use by 50% prior to and during the Fisetin dosing days. Due to drug-drug interaction, subjects may not clear the caffeine from their system properly/as usual.