Fisetin to Reduce Senescence and Mobility Impairment in PAD

NCT ID: NCT06399809

Last Updated: 2024-10-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-30
• Study Completion Date: 2027-06-30

Brief 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 peripheral artery disease (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 peripheral artery disease. In exploratory analyses, the investigators will assess whether Fisetin reduces interleukin-6 (IL-6) and novel senescent markers in adipose tissue, muscle, and/or blood.

Detailed 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 IL-6 and novel senescent markers in adipose tissue, muscle, and/or blood.

To achieve the trial's specific aims, 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.

Conditions

Peripheral Arterial Disease; Aging; Peripheral Vascular Diseases; Walking, Difficulty; Claudication

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Fisetin

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 Type: EXPERIMENTAL

Fisetin

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

The placebo will be matched to the Fisetin intervention

Interventions

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.

Intervention Type: DRUG

Placebo

The placebo will be matched to the Fisetin intervention

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

1. An ankle brachial index (ABI) less than or equal to 0.90 at baseline.

2. Vascular lab evidence of PAD (such as a toe brachial pressure less than or equal to 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 greater than 0.90 and less than or equal to 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 less than 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 less than 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 less than 500 feet or greater than1600 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 less than 7.0 g/dl, white blood count less than 2,000/mm3, white blood count greater than 20,000/mm3, platelet count less than 40,000/uL.

22. Estimated glomerular filtration rate (eGFR) less than 25 ml/min/1.73 m2

23. HemoglobinA1C great than 10 as a marker of poor diabetes control.

24. People who are Human Immunodeficiency Virus positive (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) great than 43.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Mary McDermott

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Mary McDermott, MD

Role: CONTACT

mdm608@northwestern.edu

312-503-6419

Facility Contacts

Kathryn J Domanchuk

Role: primary

k-domanchuk@northwestern.edu

312 503 6438

Mary M. McDermott

Role: backup

Other Identifiers

STU00217306

Identifier Type: -

Identifier Source: org_study_id