Senolytic + Anti-Fibrotic Agents for Osteoarthritis

Overseen By Clinical Trial Contact

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Steadman Philippon Research Institute

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

Disqualifiers: Diabetes, Fibromyalgia, Autoimmune diseases, others

Compensation: Varies

Number of Visits: 15

Duration: 30 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate two potential treatments for osteoarthritis in the knee: Fisetin, which helps clear out old cells, and Losartan, which reduces tissue thickening. The trial will test each treatment alone and in combination, compared to a standard knee injection treatment. It seeks to determine if these new approaches can improve knee function and reduce pain more effectively. Ideal candidates are those who have experienced knee osteoarthritis pain for some time and have no planned knee surgeries or recent joint injections.

As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatments work in people and measuring their effectiveness in an initial, smaller group. Participants have the opportunity to contribute to groundbreaking advancements in osteoarthritis care.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications, such as Losartan, Fisetin, and some senolytic agents, before joining. If you're on medications like opioids, certain chemotherapy drugs, or others listed, you may need to stop them for the study duration. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Fisetin, a dietary supplement, is under study for its safety and effectiveness in treating knee osteoarthritis. Current studies suggest it might help reduce the number of old cells that have stopped dividing and can cause inflammation. So far, Fisetin appears safe, but more research is needed to confirm these findings.

Losartan, typically used to treat high blood pressure, has been studied in over 3,300 patients for this purpose. It has generally been well-tolerated, with most side effects being mild. However, its specific effects on knee osteoarthritis remain under investigation. Some animal studies suggest it might aid in cartilage repair, but the results are not yet clear.

Both treatments undergo careful examination in clinical trials to ensure their safety and effectiveness for osteoarthritis. Monitoring participant responses is crucial to gather more information on their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Fisetin and Losartan for osteoarthritis because they target the condition in a unique way. Most current treatments focus on pain relief and inflammation reduction, like NSAIDs or corticosteroids. However, Fisetin is a senolytic, which means it helps remove damaged cells that contribute to aging and tissue breakdown, potentially slowing down the disease's progression. Losartan, traditionally used for high blood pressure, also has anti-fibrotic properties, which could help reduce tissue scarring and improve joint health. This combination could offer a more comprehensive approach by addressing both inflammation and the underlying cellular damage in osteoarthritis.

What evidence suggests that this trial's treatments could be effective for osteoarthritis?

Research has shown that Fisetin, one of the treatments in this trial, may help manage osteoarthritis by targeting damaged cells that no longer function properly. This can slow the disease and possibly reduce pain. Studies have also found that Losartan, another treatment option in this trial, can protect against osteoarthritis by improving cartilage health, the tissue that cushions joints. It achieves this by affecting certain processes in the body, leading to less cartilage damage. When used together, Fisetin and Losartan have significantly reduced the number of damaged cells, potentially making them more effective in treating osteoarthritis. This trial will evaluate the effects of these treatments, either alone or together, to benefit people with osteoarthritis. ^{1 2 5 6 7}

Who Is on the Research Team?

Johnny Huard, PhD

Principal Investigator

Steadman Philippon Research Institute

Marc Philippon, MD

Principal Investigator

Steadman Philippon Research Institute

Scott L Tashman, PhD

Principal Investigator

Steadman Philippon Research Institute

Are You a Good Fit for This Trial?

This trial is for ambulatory adults aged 40-85 with osteoarthritis in at least one knee, experiencing a certain level of pain. They must be able to consent and follow the study procedures. Excluded are those taking Losartan or Fisetin, anticoagulants like Warfarin, have had recent knee surgery or injections, pregnant women, individuals unable to undergo an MRI, and those with various health conditions that could interfere with the study.

Inclusion Criteria

My knee pain scores between 3 to 10, and the other knee hurts 2 points less.

I can understand and agree to the study's procedures on my own.

I have knee osteoarthritis that affects my ability to move.

Exclusion Criteria

I had a knee scope or surgery on my target knee within the last 6 months.

I have had a knee regeneration procedure in the last 6 months.

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))

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Treatment

Participants receive Fisetin or placebo for 4 days prior to BMAC injection

4 days

Treatment

Participants receive BMAC injection and continue with Losartan or placebo for 30 days

30 days

1 visit (in-person) for injection, follow-up visits as needed

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Regular follow-up visits at 14 days, 30 days, 3 months, 6 months, and 12 months post-injection

What Are the Treatments Tested in This Trial?

Interventions

• Fisetin
• Losartan

Trial Overview The trial tests the safety and effectiveness of Fisetin (a senolytic agent) and Losartan (an anti-fibrotic agent), alone or combined, compared to bone marrow stem cell injections into the knee. It's randomized and double-blind meaning participants won't know which treatment they receive.

How Is the Trial Designed?

Group I: Active Fisetin and Active Losartan Experimental Treatment 2 Interventions

Losartan 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).

Group II: Fisetin Placebo and Active Losartan Active Control 2 Interventions

Losartan 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin Placebo 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).

Group III: Active Fisetin and Losartan Placebo Active Control 2 Interventions

Losartan Placebo 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).

Group IV: Control Placebo Group 2 Interventions

Losartan placebo 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin Placebo 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).

Who Is Running the Clinical Trial?

Steadman Philippon Research Institute

Lead Sponsor

Trials

11

Recruited

700+

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Collaborator

Trials

508

Recruited

1,090,000+

Published Research Related to This Trial

Losartan potassium, an angiotensin II receptor antagonist, is effective and well-tolerated for treating hypertension, especially when combined with hydrochlorothiazide (HCTZ) for enhanced efficacy.

A new high-performance liquid chromatography method was successfully developed to simultaneously analyze losartan potassium and HCTZ along with their impurities and degradates, ensuring accurate quantification at very low levels (0.1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and validation of a stability-indicating HPLC method for the simultaneous determination of losartan potassium, hydrochlorothiazide, and their degradation products. Hertzog, DL., McCafferty, JF., Fang, X., et al.[2019]

Losartan/hydrochlorothiazide (HCTZ) is an effective fixed-dose combination therapy for hypertension, providing greater blood pressure reduction than either medication alone, and is particularly beneficial for patients with severe hypertension and left ventricular hypertrophy (LVH).

In the LIFE study, losartan-based therapy demonstrated a lower incidence of cardiovascular events and new-onset diabetes compared to atenolol, highlighting its safety and efficacy in reducing stroke risk and improving overall cardiovascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan/Hydrochlorothiazide: a review of its use in the treatment of hypertension and for stroke risk reduction in patients with hypertension and left ventricular hypertrophy. Keating, GM.[2021]

Senolytic drugs, particularly fisetin, have shown promise in reducing age-related bone density loss in a progeria mouse model, suggesting they may help combat osteoporosis in aging individuals.

The study highlights the potential of targeting senescent cells, which accumulate with age and contribute to various age-related conditions, as a strategy to improve bone health and overall quality of life in the elderly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model. Hambright, WS., Mu, X., Gao, X., et al.[2023]

Losartan is a safe and effective antihypertensive medication that blocks the angiotensin II type 1 receptor, showing similar overall adverse event rates compared to placebo in a large study of approximately 3800 patients with various conditions, including diabetes and heart failure.

The most common side effects of losartan were headache and dizziness, with dizziness being the only side effect reported more frequently than in the placebo group, indicating that losartan can be a suitable first-line treatment for hypertension, especially for patients who may not tolerate other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical safety and tolerability of losartan. Weber, M.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04210986

NCT04210986 | Senolytic Drugs Attenuate Osteoarthritis- ... The purpose of this study is to evaluate the clinical efficacy of Fisetin (FIS), a dietary supplement, in symptomatic knee osteoarthritis (OA) patients.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10184265/

Latest insights in disease-modifying osteoarthritis drugs ... This trial evaluated clinical and radiographic outcomes; the complete data have not been reported.

3. 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.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05482672

Study Details | NCT05482672 | GetHealthy-OA: A Program ... The GetHealthy-OA program combines a mind-body program with the oral supplement fisetin to potentially reduce the risk for this population by treating ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36243333/

The effects of fisetin on bone and cartilage: A systematic ... Fisetin, a natural flavonoid, has garnered attention as a promising pharmaceutical option for treating or delaying the progression of osteoporosis and OA.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8839434/

Fisetin as a Senotherapeutic Agent - PubMed Central - NIH Fisetin has recently emerged as a potential anti-inflammatory, chemopreventive, chemotherapeutic, and senotherapeutic agent, thus making it a good candidate for ...

7. ors.org ors.org/wp-content/uploads/AM25/429.pdf

429.pdf controlled clinical trial to test the safety and efficacy of Fisetin for treating knee osteoarthritis. METHODS: This study, conducted with FDA IND and IRB ...