Fisetin for Meniscus Tears

Overseen By Austin Stone, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Austin V Stone

Must not be taking: Losartan, Warfarin, Opioids, Senolytics

Disqualifiers: Pregnancy, Osteoarthritis, Diabetes, Depression, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

Trial Summary

What is the purpose of this trial?

Arthroscopic meniscal procedures are the most commonly performed orthopaedic procedure in the U.S. affecting 15% of Americans ages 10-65 years. Meniscus injury is also known to increase the risk of posttraumatic osteoarthritis (PTOA). The current randomized clinical trial will test a novel intervention after meniscal repair that combines an oral senolytic fisetin and real-time biofeedback program to restore joint loading and subsequent return to activity.

Will I have to stop taking my current medications?

The trial requires that you have been on a stable dose of your current medications for at least 2 months before starting the study. However, you may need to stop certain medications, such as Losartan, Warfarin, opioid analgesics, senolytic agents, and some chemotherapy drugs, among others. It's best to discuss your specific medications with the study team to see if any changes are needed.

What data supports the effectiveness of the drug Fisetin for meniscus tears?

Research shows that Fisetin, a natural compound found in fruits and vegetables, has beneficial effects on bone and cartilage health, and it has been shown to reduce inflammation and cartilage damage in osteoarthritis, which is a joint condition similar to meniscus tears. ^{1 2 3 4 5}

Is fisetin generally safe for humans?

Fisetin, a natural compound found in fruits and vegetables, has shown no adverse effects in animal studies and is considered safe due to its anti-inflammatory and antioxidant properties. It has been used in research for various conditions without reported toxicity. ^{6 7 8 9 10}

How does the drug fisetin differ from other treatments for meniscus tears?

Fisetin is unique because it is a natural compound found in fruits and vegetables with known antioxidant and anti-inflammatory properties, which may help in reducing inflammation and promoting healing in meniscus tears, unlike traditional treatments that may not have these additional benefits. ^{6 7 10 11 12}

Research Team

Austin Stone, MD

Principal Investigator

University of Kentucky

Eligibility Criteria

This trial is for men and women aged 18-45 who have had a surgical repair for a meniscus tear in the knee. Participants must be able to walk and follow study procedures, with stable medication use for at least 2 months before the trial. Excluded are those unable to consent or take oral meds, recent knee surgery patients, certain drug users (e.g., Warfarin), pregnant/nursing women, and individuals with severe liver/renal disease or joint diseases.

Inclusion Criteria

Subjects will be included if all the following criteria are met:

I can walk and complete physical tests.

I had surgery to repair a tear in my knee's meniscus.

Exclusion Criteria

I have received joint injections.

Subjects that have any medical condition, including laboratory findings and findings in the medical history or in the pre-study assessments, that in the opinion of the Investigator constitutes a risk or contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation or prevent the patient from fully participating in all aspects of the study.

I am not taking medications that strongly affect certain liver enzymes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the mechanobiologic intervention, including oral fisetin and real-time biofeedback, starting 8 weeks after surgery

8 weeks

Multiple visits for biofeedback sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of physical function and cartilage composition

1 year

Regular follow-up visits

Treatment Details

Interventions

• Fisetin
• Real-time Biofeedback Program

Trial Overview The clinical trial tests an intervention combining fisetin—a senolytic agent thought to help with cellular aging—and biofeedback after meniscal repair surgery. The goal is to improve joint loading and activity return post-surgery. Participants will either receive fisetin or a placebo capsule without knowing which one they're taking.

Participant Groups

Group I: Fisetin Experimental Treatment 1 Intervention

Subjects assigned to the experimental group will take approximately 20 mg/kg/day of fisetin for 2 consecutive days, followed by a 28-day senescence washout period, and then another 2-day administration. Fisetin treatment begins at 8 weeks after surgery.

Group II: Placebo Placebo Group 1 Intervention

Subjects assigned to the experimental group will take approximately 20 mg/kg/day of placebo (corn starch) for 2 consecutive days, followed by a 28-day washout period, and then another 2-day administration. Placebo treatment begins at 8 weeks after surgery.

Who Is Running the Clinical Trial?

Austin V Stone

Lead Sponsor

Trials

5

Recruited

70+

Findings from Research

Fisetin significantly reduces inflammation and oxidative stress in both an animal model (BALB/c mice) and in bovine endometrial epithelial cells (BEND) exposed to LPS, indicating its potential as a therapeutic agent against inflammatory conditions.

The protective effects of fisetin are linked to its ability to inhibit TLR4-mediated pathways and activate the Nrf2/HO-1 pathway, which together help reduce harmful reactive oxygen species (ROS) and pro-inflammatory cytokines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin Ameliorates the Inflammation and Oxidative Stress in Lipopolysaccharide-Induced Endometritis. Jiang, K., Yang, J., Xue, G., et al.[2022]

Fisetin, a bioflavonoid found in fruits and vegetables, significantly reduced blood glucose and glycosylated hemoglobin levels in diabetic rats after 30 days of treatment at a dose of 10 mg/kg, while also increasing plasma insulin levels.

The study demonstrated that fisetin helps regulate carbohydrate metabolism by normalizing the activities of key enzymes in the liver and kidneys of diabetic rats, suggesting its potential as a therapeutic agent for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. Prasath, GS., Subramanian, SP.[2021]

Fisetin, a natural compound found in fruits and vegetables, significantly inhibits the growth and DNA synthesis of human colon cancer cells (HT-29), with a 79% reduction in cell number observed after 72 hours at a concentration of 60 micromol/L.

The mechanism of action involves disrupting cell cycle progression, particularly causing a G(1) to S phase arrest and a G(2)/M phase block, which is linked to decreased activity of cyclin-dependent kinases (CDK) and changes in retinoblastoma protein phosphorylation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. Lu, X., Jung, Ji., Cho, HJ., et al.[2023]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice. [2022]

2. India pubmed.ncbi.nlm.nih.gov

Quercetin prevent proteoglycan destruction by inhibits matrix metalloproteinase-9, matrix metalloproteinase-13, a disintegrin and metalloproteinase with thrombospondin motifs-5 expressions on osteoarthritis model rats. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

The effects of fisetin on bone and cartilage: A systematic review. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Neuroprotective potential of fisetin in an experimental model of spinal cord injury: via modulation of NF-κB/IκBα pathway. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Tamarindus indica Seed Extract-Based Botanical Compositions Alleviate Knee Pain and Improve Joint Function in Mild-to-Moderate Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Clinical Study. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

3,3',4',5,5'-Pentahydroxyflavone is a potent inhibitor of amyloid β fibril formation. [2021]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Fisetin Ameliorates the Inflammation and Oxidative Stress in Lipopolysaccharide-Induced Endometritis. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Fisetin and Its Role in Chronic Diseases. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

A novel 4'-brominated derivative of fisetin induces cell cycle arrest and apoptosis and inhibits EGFR/ERK1/2/STAT3 pathways in non-small-cell lung cancer without any adverse effects in mice. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice. [2021]