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

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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.

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 the treatment with Losartan and related agents generally safe for humans?

Losartan, used for high blood pressure and other conditions, is generally well-tolerated in humans, but common side effects include fatigue, high potassium levels, and low blood pressure. It has been shown to have beneficial effects in various studies, including improving physical function in older adults and providing protective effects on bones in animal studies. ^{1 2 3 4 5}

How is the senolytic and anti-fibrotic drug for osteoarthritis different from other treatments?

This treatment is unique because it targets and removes senescent cells (old cells that no longer function properly) which accumulate with age and contribute to osteoarthritis. Unlike traditional treatments that mainly address symptoms, senolytics like fisetin work by eliminating these harmful cells, potentially reducing inflammation and slowing disease progression. ^{6 7 8 9 10}

What evidence supports the effectiveness of the drug Losartan for osteoarthritis?

Research shows that Losartan, a drug used to treat high blood pressure, may also help improve bone structure and metabolism, which could be beneficial for conditions like osteoarthritis. In studies with animals, Losartan improved bone health and reduced inflammation, suggesting it might help with joint issues. ^{1 3 4 5 11}

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 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]

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]

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]

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]

Citations

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

Clinical safety and tolerability of losartan. [2019]

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

Serum Concentrations of Losartan Metabolites Correlate With Improved Physical Function in a Pilot Study of Prefrail Older Adults. [2023]

3. New Zealand 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. [2021]

4. England 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. [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade. [2021]

6. India pubmed.ncbi.nlm.nih.gov

Effect of chronic treatment with losartan on streptozotocin induced diabetic rats. [2013]

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

New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. [2021]

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

The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24 -/- Progeria Mouse Model. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence. [2021]

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

Prospective Selective Mechanism of Emerging Senolytic Agents Derived from Flavonoids. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Senolytic drugs: from discovery to translation. [2022]