Fisetin for PAD

(FIRST Trial)

Overseen By Mary McDermott, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: Warfarin, others

Disqualifiers: Amputation, Critical limb ischemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

34 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Fisetin, a natural compound in fruits like strawberries, can help people with peripheral artery disease (PAD) walk longer distances. Researchers aim to determine if Fisetin reduces senescent cells, which have stopped dividing and can cause inflammation. The trial will also examine whether Fisetin lowers levels of certain inflammatory markers in the body. Individuals diagnosed with PAD who often struggle with walking might be suitable candidates for this trial. As a Phase 2 trial, this research focuses on assessing Fisetin's effectiveness in an initial, smaller group, providing an opportunity to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires that people taking certain medications, like warfarin and other drugs that are sensitive to specific enzymes, must stop taking them for at least two days before and ten hours after each study drug dose. If you're on these medications, you'll need to pause them during the trial as specified.

Is there any evidence suggesting that Fisetin is likely to be safe for humans?

Previous studies have shown fisetin to be very safe. This natural compound occurs in fruits like strawberries and apples. Among three similar treatments being tested, fisetin ranks as the safest, meaning people generally tolerate it well, with fewer reported side effects.

Research indicates that fisetin can help remove old, damaged cells, potentially improving health and reducing aging-related issues. Although still under study, early findings suggest it is well-tolerated in humans, providing confidence in its safety for those considering participation in a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PAD?

Unlike the standard treatments for Peripheral Artery Disease (PAD), which often include medications like statins, antiplatelet agents, or cilostazol, Fisetin offers a novel approach. Fisetin is a natural compound found in fruits and vegetables, and it acts as a senolytic, targeting and eliminating senescent cells that contribute to inflammation and vascular aging. Researchers are excited about Fisetin because it could potentially improve blood flow and reduce inflammation without the side effects typically associated with long-term pharmaceutical use. This unique mechanism of action sets Fisetin apart and holds promise for more effective and safer management of PAD.

What evidence suggests that Fisetin might be an effective treatment for PAD?

Research has shown that fisetin, a natural compound in some fruits and vegetables, might help manage several chronic diseases by reducing senescent cells. These cells have stopped dividing and can contribute to aging and disease. Studies in mice demonstrated that fisetin can improve artery function by reducing these cells, leading to better blood flow and less stiffness. This trial will test fisetin as a potential treatment for peripheral artery disease (PAD), with participants receiving either fisetin or a placebo. The aim is to determine if fisetin can help people with PAD move more easily and walk further by improving blood vessel health. Early findings also indicate that reducing senescent cells could lower inflammation, as shown by decreased levels of interleukin-6, a marker of inflammation, in the body. Although more research in humans is needed, these initial results are promising for fisetin as a potential treatment for PAD. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

This trial is for people with peripheral artery disease (PAD), which can cause limited mobility and difficulty walking. Participants must have specific vascular lab evidence of PAD or a drop in ABI after the heel-rise test. It's not suitable for those who don't meet these criteria.

Inclusion Criteria

My ankle-brachial index (ABI) is 0.90 or lower.

I have been diagnosed with PAD based on vascular tests or angiography.

My ABI is between 0.90 and 1.00, and it drops by 20% or more after a physical test.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Fisetin or placebo for two days every 14 days over a 4-month period

16 weeks

Bi-weekly visits for dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Fisetin

Trial Overview The study tests if Fisetin, a compound thought to reduce cell aging, can decrease senescent cells and improve walking distance over six minutes compared to a placebo. The effects on inflammation markers and other aging indicators will also be explored.

How Is the Trial Designed?

Group I: Fisetin Experimental Treatment 1 Intervention

Sharp Clinical Services will provide fisetin (100 mg capsules). Randomized participants will receive fisetin 20 mgs/kg once daily for two days, followed by 12 days without therapy. Fisetin will be dosed in 100 mg tablets. Dosing will be rounded to the nearest 100 mg. For example, a 73 kg participant with a dose of 1,460 mg (i.e.73 kg x 20 mg) receives 1,500 mgs daily (i.e. 15 x 100 mg capsules) for two days every 14 days.

Group II: Placebo Placebo Group 1 Intervention

Sharp Clinical Services will provide placebo (100 mg capsules). Randomized participants will receive placebo 20 mgs/kg once daily for two days, followed by 12 days without therapy. Placebo will be dosed in 100 mg tablets. Dosing will be rounded to the nearest 100 mg. For example, a 73 kg participant with a dose of 1,460 mg (i.e.73 kg x 20 mg) receives 1,500 mgs daily (i.e. 15 x 100 mg capsules) for two days every 14 days.

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Published Research Related to This Trial

Fisetin, a natural flavonoid, effectively reduces inflammation by inhibiting proinflammatory mediators and cytokines in macrophages, as demonstrated in a study using LPS-stimulated RAW 264.7 cells.

The study also showed that fisetin protects against LPS-induced mortality and inflammation in zebrafish larvae by modulating the GSK-3β/β-catenin and NF-κB signaling pathways, highlighting its potential as an anti-inflammatory agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock. Molagoda, IMN., Jayasingha, JACC., Choi, YH., et al.[2023]

The self-nanoemulsifying drug delivery system (SNEDDS) significantly enhanced the effectiveness of fisetin in improving behavioral changes in rats induced by rotenone, outperforming naïve fisetin in both efficacy and bioavailability.

SNEDDS formulation not only improved the anti-Parkinsonian effects of fisetin at lower doses but also demonstrated neuroprotective properties by reducing neuronal damage, indicating a promising approach for enhancing the therapeutic potential of fisetin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved neuroprotective activity of Fisetin through SNEDDS in ameliorating the behavioral alterations produced in rotenone-induced Parkinson's model. Kumar, R., Kumar, R., Khurana, N., et al.[2022]

Fisetin, an anti-inflammatory flavonoid, effectively reduces inflammation in human gingival fibroblasts by inhibiting the activation of MAPK pathways and decreasing COX-2 expression when exposed to lipopolysaccharide (LPS).

The study demonstrated that fisetin does not negatively impact cell viability while significantly lowering prostaglandin E2 synthesis, suggesting its potential as a safe therapeutic option for managing periodontal disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory activity of fisetin in human gingival fibroblasts treated with lipopolysaccharide. Gutiérrez-Venegas, G., Contreras-Sánchez, A., Ventura-Arroyo, JA.[2021]

Fisetin, a flavonoid, effectively reduces inflammation in macrophage-like cells by decreasing the release of nitric oxide and lowering the levels of inflammatory markers without being toxic to the cells.

The anti-inflammatory effects of fisetin are linked to its ability to inhibit key signaling pathways, specifically by suppressing the activities of Src and Syk, which are involved in the activation of NF-κB, a major regulator of inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin Suppresses Macrophage-Mediated Inflammatory Responses by Blockade of Src and Syk. Kim, JH., Kim, MY., Kim, JH., et al.[2020]

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 (Fis) demonstrated the strongest anti-inflammatory effects among the flavonols tested, inhibiting nitric oxide production by 52% at a concentration of 20 μM in lipopolysaccharide-stimulated RAW264.7 cells.

The study revealed that these flavonols, particularly Fis, work by inhibiting key inflammatory pathways (NF-κB and MAPK) and reducing pro-inflammatory markers like TNF-α and IL-6, suggesting their potential use in preventing or treating inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory activity of flavonols via inhibiting MAPK and NF-κB signaling pathways in RAW264.7 macrophages. Zhong, R., Miao, L., Zhang, H., et al.[2022]

Fisetin-nanostructured lipid carriers (NLCs) significantly enhance the delivery and efficacy of fisetin against metastatic melanoma, showing a 3.2 times lower IC50 value and 1.8 times higher drug uptake in cancer cells compared to pure fisetin.

In vivo studies revealed that Fis-NLCs resulted in 5.9- and 10.7-fold greater inhibition of melanoma metastasis in the lungs and liver, respectively, indicating their potential as an effective treatment strategy for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin-Loaded Nanostructured Lipid Carriers: Formulation and Evaluations against Advanced and Metastatic Melanoma. Kumar, H., Chand, P., Pachal, S., et al.[2023]

In a mouse model of acute pulmonary inflammation, the flavonoid fisetin significantly reduced levels of inflammatory markers and mediators, outperforming other flavonoids and the glucocorticoid dexamethasone.

Fisetin's ability to lower myeloperoxidase levels and gene expression of inflammatory mediators suggests it could be a promising candidate for treating pulmonary inflammatory diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of LPS-induced pulmonary inflammation by specific flavonoids. Geraets, L., Haegens, A., Brauers, K., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06399809

NCT06399809 | Fisetin to Reduce Senescence and ... The investigators propose a pilot randomized trial to gather preliminary data to test the hypothesis that Fisetin will reduce abundance of senescent cells ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0047637424000952

Fisetin as a senotherapeutic agent: Evidence and ... Our review of available data suggests that targeting senescent cells with fisetin offers a promising strategy for managing multiple chronic diseases.

3. reporter.nih.gov reporter.nih.gov/project-details/10691354

FIsetin to Reduce Senescence and mobility impairmenT in PAD We hypothesize that reducing senescent cells will improve walking performance and prevent disability in people with PAD. Fisetin is a flavanol, present in ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06399809/fisetin-to-reduce-senescence-and-mobility-impairment-in-pad

Fisetin to Reduce Senescence and Mobility Impairment in ... The investigators propose a pilot randomized trial to gather preliminary data to test the hypothesis that Fisetin will reduce abundance of ...

5. researchgate.net researchgate.net/publication/376350086_Intermittent_supplementation_with_fisetin_improves_arterial_function_in_old_mice_by_decreasing_cellular_senescence

Intermittent supplementation with fisetin improves arterial ... Fisetin, another flavonoid, has recently been shown to ameliorate endothelial dysfunction and arterial stiffness in old mice by reducing cell senescence 133 , ...

6. withpower.com withpower.com/trial/phase-2-aging-8-2023-1d19d

Fisetin for Improved Vascular Function in Aging This trial tests if fisetin, a natural substance from fruits and vegetables, can improve blood vessel health and reduce artery stiffness in older adults.