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Study Description

Osteoarthritis (OA) is a progressive joint disease leading to cartilage damage, pain, and loss of function. While many stem cell therapies for OA are under investigation, none are currently FDA-approved for modifying the course of the disease. Of the many adult stem cell types potentially applicable to OA, bone marrow stem cells (BMSCs) from bone marrow aspirate concentrate (BMC) are the most clinically translatable (and are already in clinical use) since they can be harvested using minimally invasive technology and do not require in vitro expansion. There is, however, significant potential for improving efficacy of BMSC treatment for OA. The number of senescent cells in BMC increases with age and OA, and these cells release pro-inflammatory cytokines/chemokines, proteases, and other senescence-associated secretory phenotypes (SASP) that can impair stem cell function and likely contribute to OA development/progression. Based on the previous findings, the senolytic agents can delay OA in a preclinical model, and also blocking fibrosis with Losartan (a TGF-β1blocker) can improve cartilage repair by promoting regeneration of hyaline cartilage while reducing the amount of fibrocartilage. Thus, this study hypothesizes that the administration of senolytic and/or anti-fibrotic agents will enhance the beneficial effect of BMSCs for treating OA.

This phase I/II trial will evaluate the safety and efficacy of Fisetin (a senolytic dietary supplement) and Losartan (an anti-fibrotic drug), used either individually or in combination, for improving the clinical efficacy of BMSCs in the treatment of knee osteoarthritis. The senolytic (Fisetin 1000mg/day, previously FDA IND approved) regimen will be cycles of 2 days on/28 days off, administered before and 3 months after BMSC treatment. The anti-fibrotic (Losartan, 25mg/day, previously IND-exempted) will be administered for 30 days starting immediately after BMSC treatment. OA knee joints will undergo MRI at baseline and 18 months post-treatment to assess changes in cartilage morphology and structure over time. Patient-reported outcomes for pain and function will be collected at baseline and 3, 6, 12 & 18 months. Joint and cartilage function will be assessed using video-motion analysis at baseline and 18 months. OA biomarkers related to cartilage degeneration, inflammation, and pain will be assessed at baseline and 18 months. Blood and synovial fluid will be evaluated at baseline, 4 days, and 18 months after treatment to assess changes in cellular senescence and OA biomarkers.

ELIGIBILITY CRITERIA:

Ages Eligible for Study: 40 Years to 85 Years (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

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. Mean 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 24-hour mean pain score (on the 11-point Numeric Rating Scale) for at least five of the seven days during the baseline period.

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:
a. Currently taking Losartan;
b. Currently taking Warfarin or related anticoagulants;
c. Currently taking Lithium;
d. Opioid analgesics taken in the past 8 weeks and are not willing to discontinue these medications through the duration of the study;
e. 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;
f. 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;
g. 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.

Study Design:

Allocation:       Randomized

Intervention Model: Parallel Assignment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose: Treatment

Study Location(s):

The Steadman Clinic, Vail, Colorado, United States, 81657

Study Website:

https://clinicaltrials.gov/ct2/show/NCT04815902?term=NCT04815902&draw=2&rank=1