Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women

Study Overview
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Brief Summary
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This is a pilot study to evaluate whether targeting inflammation will help reduce markers of insulin resistance inflammation, bone resorption and physical dysfunction in elderly women with gait disturbance. Positive results of this study would lead to the development of a larger clinical trial examining the effects of this intervention on age-related dysfunction.

Detailed Description
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To the researchers' knowledge, there are no published studies utilizing Fisetin in alteration of frailty markers. Several studies involve use of Fisetin for its anti-oxidative and anti-apoptotic effects in animal models. Fisetin may reduce oxidative stress, alleviate hyperglycemia, and improve kidney function. No one has evaluated the biologic markers of inflammation and frailty in older postmenopausal women. The researchers plan to evaluate markers of frailty and markers of inflammation, insulin resistance, and bone resorption while maintaining bone formation in older postmenopausal women.

Official Title
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AFFIRM: A Phase 2 Randomized, Placebo-Controlled Study of Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Women

Conditions
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Frail Elderly Syndrome

Intervention / Treatment
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* Dietary Supplement: Fisetin
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Healthy postmenopausal women Age ≥ 70 years Exclusion Criteria Abnormality in any of the screening laboratory studies (see below) Presence of significant liver or renal disease Malignancy (including myeloma) Malabsorption Hypoparathyroidism Hyperparathyroidism Acromegaly Cushing's syndrome Hypopituitarism Gastric bypass/reduction Malabsorption issues Crohn's Myopathies (increased or low calcium, vitamin D deficiency, elevated creatine kinase or ESR) If diabetic AND on sulfonylureas (like glipizide, glimepiride, glyburide), SGLT2 inhibitors (like dapagliflozin and empagliflozin), or insulin Undergoing treatment with any medications that affect bone turnover, including the following: adrenocorticosteroids (> 3 months at any time or > 10 days within the previous yr), anticonvulsant therapy (within the previous year), pharmacological doses of thyroid hormone (causing decline of thyroid stimulating hormone below normal), calcium supplementation of > 1200 mg/d (within the preceding 3 months), bisphosphonates (within the past 3 yrs), denosumab, estrogen (E) therapy or treatment with a selective E receptor modulator, or teriparatide (within the past yr). Subjects with a fracture within the past year Subjects taking potentially senolytic agents within the last year: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax Subjects currently taking drugs that induce cellular senescence: alkylating agents, anthracyclines, platins, other chemotherapy QTc >450 msec Inability to provide informed consent Total bilirubin >2X upper limit Inability to tolerate oral medication eGFR < 15 ml/ min/ 1.73 m2 Subjects on therapeutic doses of anticoagulants (e.g., warfarin, heparin, low molecular weight heparin, factor Xa inhibitors, etc.) Subjects taking the following antimicrobial agents: Aminoglycosides, Azole antifungals (fluconazole, miconazole, voriconazole, itraconazole), Macrolides (clarithromycin, erythromycin), Antivirals (nelfinavir, indinavir, saquinavir, ritonavir, elbasvir/grazoprevir), Rifampin Subjects taking proton pump inhibitors who are unable or unwilling to reduce or hold therapy prior to and during the 2-day Fisetin dosing Subjects taking the following other drugs if they cannot be held for at least 2 days before and during administration of Fisetin: digoxin, lithium, all statins, repaglidine, bosentan, gemfibrozil, olmesartan, enalapril, valsartan, methotrexate, corticosteroids, thyroid hormones, eluxadoline, eltrombopag, nitroglycerin, pioglitazone, glyburide, enzalutamide, ezetimibe, colchicine, imatinib, cyclosporine, tacolimus, sirolimus, carbamazepine, flecainide, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, heparin, full dose ASA, clopidogrel, celecoxib, desipramine, thioridazine, venlafaxine, tizanidine, atomoxetine, voriconazole, citalopram, diazepam, escitalopram, propranolol, clozapine, cyclobenzaprine, mexiletine, olanzapine, ondansetron, riluzole In order to ensure vitamin D sufficiency, we will also exclude subjects with serum 25-hydroxyvitamin D levels of < 20 ng/ml.

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Fisetin 20/mg/kg/day, orally for 2 consecutive days, for 2 consecutive months. | Dietary Supplement: Fisetin<br>* Flavonoid Family<br>|
| Placebo Comparator: Placebo<br>Placebo capsules orally for 2 consecutive days, for 2 consecutive months. | Drug: Placebo oral capsule<br>* Placebo<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improved 6 minute walk | Improved gait speed | One Month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Frailty, Inflammation