Fisetin to Reduce Senescence and Mobility Impairment in PAD

Aging Clinical Trial

— FIRST  

Official title:

Fisetin to Reduce Senescence and Mobility Impairment in Peripheral Artery Disease: the FIRST Pilot Randomized Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06399809
• Other study ID #: STU00217306
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: June 1, 2024
• Est. completion date: June 30, 2027

Study information

• Verified date: April 2024
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators propose a pilot randomized trial to gather preliminary data to test the hypothesis that Fisetin will reduce abundance of senescent cells in blood, skeletal muscle, and both subcutaneous and inter muscular adipose tissue and improve 6-minute walk distance in 34 people with PAD. the investigators will determine whether greater declines in abundance of cells with senescent markers are associated with greater improvement in 6-minute walk distance in people with PAD. In exploratory analyses, the investigators will assess whether Fisetin reduces SASP and novel senescent markers in adipose tissue, muscle, and/or blood.

Description:

Fisetin is a flavanol, present in strawberries, apples, and persimmons, that destroys senescent cells (i.e. a senolytic therapy). Of three senolytic therapies being tested in clinical trials, Fisetin has the best safety profile. Hence, the investigators propose a pilot randomized trial to gather preliminary data to test the hypothesis that Fisetin will reduce abundance of senescent cells in blood, skeletal muscle, and both subcutaneous and inter muscular adipose tissue and improve 6-minute walk distance in 34 people with PAD. The investigators will determine whether greater declines in abundance of cells with senescent markers are associated with greater improvement in 6-minute walk distance in people with PAD. In exploratory analyses, the investigators will assess whether Fisetin reduces SASP and novel senescent markers in adipose tissue, muscle, and/or blood.

To achieve the trial's specific aims, the investigators will randomize 34 participants age 50 and older with PAD to one of two groups: Fisetin vs placebo. Participants will be followed for four months.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 34
• Est. completion date: June 30, 2027
• Est. primary completion date: November 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

First, all participants will be age 50 and older. Second, all participants will have PAD. PAD will be defined as:

1. An ABI < =0.90 at baseline.

2. Vascular lab evidence of PAD (such as a toe brachial pressure < 0.70 or an ankle brachial index less than or equal to 0.90), or angiographic evidence of PAD defined as at least 70% stenosis of an artery supplying the lower extremities.

3. An ABI of >0.90 and <=1.00 who experience a 20% or greater drop in ABI in either leg after the heel-rise test will also be included.

Exclusion Criteria:

1. Above- or below-knee amputation

2. Critical limb ischemia defined as an ABI <0.40 with signs or symptoms of critical limb ischemia

3. Wheelchair confinement or requiring a walker to ambulate

4. Walking is limited by a symptom other than PAD

5. Current foot ulcer on bottom of foot

6. Failure to successfully complete the study run-in

7. Planned major surgery, coronary or leg revascularization during the next five months

8. Major surgery, coronary or leg revascularization or major cardiovascular event in the previous three months

9. Major medical illness including lung disease requiring oxygen, Parkinson's disease, a life-threatening illness with life expectancy less than six months, or cancer requiring treatment in the previous two years. [NOTE: potential participants may still qualify if they have had treatment for an early stage cancer in the past two years and the prognosis is excellent. Participants who require oxygen only at night may still qualify.]

10. Mini-Mental Status Examination (MMSE) score < 23

11. Allergy to fisetin

12. Currently taking fisetin or has taken fisetin in previous three months

13. Non-English speaking

14. Current participation in or completion of a clinical trial intervention in the previous three months. [NOTE: after completing a stem cell or gene therapy intervention, participants will become eligible after the final study follow-up visit of the stem cell or gene therapy study so long as at least six months have passed since the final intervention administration. After completing a clinical trial (other than stem cell or gene therapy), participants will be eligible after the final study intervention as long as at least three months have passed since the final intervention of the trial.]

15. Visual impairment that limits walking ability.

16. Six-minute walk distance of <500 feet or >1600 feet.

17. Participation in a supervised treadmill exercise program in previous three months.

18. Participants may be excluded if they are unwilling to undergo a fat biopsy. However, if investigators find recruitment significantly slows due to this exclusion, participants may still be able to participate in the trial if they refuse the fat biopsy.

19. Women who are not menopausal will be excluded. Menopause is defined as absence of a menstrual period in the past 12 months.

20. People with a bilirubin above 2.2 mg/dl, with serum aspartate transaminase (AST) or alanine aminotransferase (ALT) more than four times the upper limit of normal.

21. Hemoglobin < 7.0 g/dl, white blood count < 2,000/mm3, white blood count > 20,000/mm3, platelet count < 40,000/uL.

22. eGFR< 25 ml/min/1.73 m2

23. HemoglobinA1C > 10 as a marker of poor diabetes control.

24. People who are HIV+ and people with active hepatitis B or active hepatitis C infections who do not have a low viral load.

25. People taking warfarin and other sensitive substrates of CYP2C9, CYP2C19, or CYP1A2 that have a narrow therapeutic window will be excluded, unless the drug can be held for at least two days prior to the first day of each study drug administration and can continue to be held for ten hours after the second dose of study drug administration for each of the two days of study drug dosing.

26. Body mass index (BMI) >43.

27. In addition to the above criteria, investigator discretion will be used to determine if the trial is unsafe or not a good fit for the potential participant. In some instances, patients whose medications or laboratory data meet exclusion criteria may participate at the Principal Investigator's discretion.

Related Conditions & MeSH terms

• Aging
• Mobility Limitation
• Peripheral Arterial Disease
• Peripheral Vascular Diseases
• Vascular Diseases
• Walking, Difficulty

Intervention

Drug:
• Fisetin
Fisetin is a flavanol, present in strawberries, apples, and persimmons, that destroys senescent cells (i.e. a senolytic therapy). Of three senolytic therapies being tested in clinical trials, fisetin has the best safety profile.
• Placebo
The placebo will be matched to the Fisetin intervention

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Northwestern University

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Abundance of SASP markers	Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin changes abundance of SASP markers in blood at 4-month follow-up. Quantitative reverse transcription-PCR (qRT-PCR) will be performed by Dr. Peterson's lab for RNA encoding SASP markers in adipose tissue, including interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), IL-1a, growth differentiation factor 15, and IL-6.	Measured at baseline and 4 months
Other	Abundance of oxylipin dihomo-15d-PGJ2	Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin changes abundance of oxylipin dihomo-15d-PGJ2 in blood at 4-month follow-up.	Measured at baseline and 4 months
Other	SASP mRNA abundance	Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin changes SASP mRNA abundance in gastrocnemius muscle and lower extremity adipose tissue at 4-month follow-up. qRT-PCR will quantify SASP mRNAs as described for fat tissue	Measured at baseline and 4 months
Other	Gastrocnemius muscle fibrosis	Among older people with PAD, the investigators will determine whether reduced senescent cell abundance and whether reduced SASP factor abundance in blood, gastrocnemius muscle, and adipose tissue, respectively, are correlated with reduced gastrocnemius muscle fibrosis at 4-month follow up. Antibodies to collagen I and III will quantify extracellular matrix composition. Picrosirius Red histochemistry will quantify total fibrous collagen, with polarized light to assess collagen organization.	Measured at baseline and 4 months
Other	Gastrocnemius muscle collagen	Among older people with PAD, the investigators will determine whether reduced senescent cell abundance and whether reduced SASP factor abundance in blood, gastrocnemius muscle, and adipose tissue, respectively, are correlated with reduced gastrocnemius muscle collagen at 4-month follow up. Antibodies to collagen I and III will quantify extracellular matrix composition. Picrosirius Red histochemistry will quantify total fibrous collagen, with polarized light to assess collagen organization.	Measured at baseline and 4 months
Other	Abundance of cells with central nuclei	Among older people with PAD, the investigators will determine whether reduced senescent cell abundance and whether reduced SASP factor abundance in blood, gastrocnemius muscle, and adipose tissue, respectively, are correlated with a reduced abundance of cells with central nuclei at 4-month follow up. Muscle fiber cross-sectional area will be quantified and DAPI staining performed for centrally nucleated fibers, a marker of ischemic injury/regeneration.	Measured at baseline and 4 months
Other	Abundance of cells with increased myofiber size	Among older people with PAD, the investigators will determine whether reduced senescent cell abundance and whether reduced SASP factor abundance in blood, gastrocnemius muscle, and adipose tissue, respectively, are correlated with a reduced abundance of cells with increased myofiber size at 4-month follow up.Muscle fiber cross-sectional area will be quantified and DAPI staining performed for centrally nucleated fibers, a marker of ischemic injury/regeneration.	Measured at baseline and 4 months
Primary	Six-minute Walk Distance	Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin improves six-minute walk distance at 4-month follow-up	Measured at baseline and 4 month follow-up
Secondary	Gastrocnemius perfusion	Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin improves gastrocnemius perfusion at 4-month follow-up. We will use arterial spin labeling with MRI and post-cuff occlusion hyperemia to measure changes in calf perfusion at 3 Tesla. MRI perfusion will be measured using cuff occlusion hyperemia while the participant is supine.	Measured at baseline and 4 months
Secondary	Hand Grip Strength	Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin improves hand grip strength at 4-month follow-up.; readouts.	Measured at baseline and 4 months
Secondary	Short physical performance battery (SPPB)	Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin improves the short physical performance battery (SPPB) at 4-month follow-up. SPPB range, range 0-12, 12-best	Measured at baseline and 4 months
Secondary	Number of cells with senescence markers	Among older people with PAD, the investigators will determine whether, compared to placebo, fisetin decreases cells with senescence markers in lower extremity adipose tissue, blood (CD3+ T lymphocytes), and gastrocnemius muscle at 4-month follow-up.	Measured at baseline and 4 months