Healthy Clinical Trial
Official title:
Pharmacokinetics, Safety, and Efficacy of Fisetin - A Phase I and Pilot Phase IIa Study
The accumulation of senescent cells with age is a central mechanism that contributes to the development of chronic diseases, primarily by driving systemic chronic inflammation. Senolytic compounds such as fisetin can selectively target senescent cells for elimination and reduce multiple age-related pathologies in animal models. We will conduct a clinical trial in healthy volunteers and older patients with multiple chronic diseases. The participants will receive fisetin or placebo for two days, after which they will be examined at regular intervals for up to three months. We will investigate how fisetin is absorbed and metabolized by the body, and whether fisetin is safe. We will also identify methods to best measure the effect of fisetin on chronic inflammation, senescent cells, and general health.
Status | Not yet recruiting |
Enrollment | 60 |
Est. completion date | June 1, 2034 |
Est. primary completion date | December 31, 2026 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 20 Years and older |
Eligibility | Healthy volunteers: Inclusion Criteria: - Aged 20-35 years - suPAR levels <3.5 ng/mL (± 15% corresponding to assay variation) - Able to cooperate cognitively - Able to read and understand Danish - Women of childbearing potential must use effective contraception Exclusion Criteria: - Body weight >100 kg - Inability to swallow pills - Pregnant and/or lactating - Known hypersensitivity or allergy to fisetin or excipients in the placebo capsules - Presence of any condition that the investigator believes would put the subject at risk or would preclude the participant from successfully completing all aspects of the trial - Presence of known chronic diagnosis - Active acute illness - Prescribed medication, except contraceptives - Previous cancer diagnosis or treatment - Use of senolytic and other "anti-aging" supplements Older patients with multimorbidity: Inclusion Criteria: At screening #1 during hospital admission: - Acutely hospitalized medical patient - Age =65 years - suPAR >5 ng/mL (± 15% corresponding to assay variation) - Multimorbidity (=2 chronic diagnoses) - Able to cooperate cognitively - Able to read and understand Danish At screening #2 28 days after hospital discharge: - suPAR >5 ng/mL (± 15% corresponding to assay variation) Exclusion Criteria: At screening #1 during hospital admission: - Body weight >100 kg - Inability to swallow pills - Known human immunodeficiency virus infection, active hepatitis B or C infection, invasive fungal infection - Uncontrolled (as per clinical judgment) pleural/pericardial effusions or ascites - New/active invasive cancer except non-melanoma skin cancers - Active cancer treatment or disseminated cancer - Known condition associated with major immunodeficiency - Known hypersensitivity or allergy to fisetin or excipients in the placebo capsules - Use of senolytic and other "anti-aging" supplements At screening #2 28 days after hospital discharge: - Body weight >100 kg - CRP >30 mg/L (± 15% corresponding to assay variation) - Inability to swallow pills - Presence of any condition, or abnormal routine biochemistry test, that the investigator believes would put the subject at risk or would preclude the patient from successfully completing all aspects of the trial - Unstable (as per clinical judgment) major disorders, e.g., cardiovascular, renal, endocrine, immunological, hepatic disorder, or cancer - Estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m2 or as per clinical judgment (e.g., risk of acute kidney injury) - Human immunodeficiency virus infection, known active hepatitis B or C infection, invasive fungal infection - Uncontrolled (as per clinical judgment) pleural/pericardial effusions or ascites - New/active invasive cancer except non-melanoma skin cancers - Active cancer treatment or disseminated cancer - Known condition associated with major immunodeficiency - Known hypersensitivity or allergy to fisetin or excipients in the placebo capsules - Subjects taking strong inhibitors or inducers of CYP3A4 or as per clinical judgment - Subjects taking specified substrates with a narrow therapeutic range for CYP3A4 or as per clinical judgment - Subjects taking specified inhibitors, inducers, or substrates of CYP2D6, CYP2C9, or CYP2C8, or as per clinical judgment - Subjects regularly using drug classes or specific medications or as per clinical judgment - Use of senolytic and other "anti-aging" supplements |
Country | Name | City | State |
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n/a |
Lead Sponsor | Collaborator |
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Ove Andersen | Mayo Clinic, University of Southern Denmark |
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Population-based pharmacokinetic model for fisetin and metabolites | To develop a population-based pharmacokinetic (popPK) model for fisetin and its main metabolites in healthy volunteers and older patients, covariates such as body weight, body composition, age, and CYP inducers/inhibitors will be tested for influence on interindividual variability. | 24 hours | |
Primary | Adverse events | Number of participants to experience adverse events | Day 1 to 3 | |
Primary | suPAR | The change in plasma levels of suPAR and a sample size calculation based on these data. | Day 1 to 29 | |
Secondary | Population-based PKPD model for fisetin | Changes in any of the measured biomarkers and the relationship between the pharmacokinetics and pharmacodynamics of fisetin will be investigated using population PKPD modeling. | 24 hours | |
Secondary | Renal excretion of fisetin and its main metabolites | Urinary levels of fisetin and its main metabolites | 24 hours | |
Secondary | Symptoms and adverse events | Number of participants to experience symptoms and clinically significant changes in vital signs (i.e., blood pressure, pulse). | Day 1 to 3 | |
Secondary | SASP factors and inflammation markers | The change in plasma levels of SASP factors and inflammation markers (e.g., cytokines, chemokines, proteases, growth factors). | Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84. | |
Secondary | Senescence | The change in expression levels of senescence markers (e.g., p16INK4a, p21CIP1/WAF1, SA-B-gal) in immune cells and tissue biopsies (skin and adipose tissue). | Healthy volunteers: day 1, 29. Older patients: day 1, 8, 15, 29, 84. | |
Secondary | Senolysis | The change in expression levels of senolysis markers (e.g., leukotriene B4, dihomo-15d-PGJ2 (oxylipin or 1a,1b-dihomo-15-deoxy-D12,14-prostaglandin J2), and 15-Deoxy-delta 12, 14-prostaglandin J2). | Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 84. | |
Secondary | Aging markers | The change in plasma levels of aging markers (e.g., a-klotho, fibroblast growth factor 21). | Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84. | |
Secondary | Clinical markers | The change in levels of routine biochemistry markers (e.g., alanine aminotransferase, albumin, alkaline phosphatase, bilirubin, blood urea nitrogen, coagulation factors II, VII and X and International Normalized Ratio, CRP, creatinine, hemoglobin, lactate dehydrogenase, mean corpuscular hemoglobin concentration, mean corpuscular volume, neutrophils, potassium, sodium, thrombocytes, white blood cell count, cholesterol (total, low-density lipoproteins, high-density lipoproteins), triglycerides, and hemoglobin A1c). | Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84. | |
Secondary | Frailty Index OutRef | The change in frailty status calculated as Frailty Index OutREF (FI-OutRef). | Healthy volunteers: day 1, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84. | |
Secondary | Frailty Index | The change in frailty status calculated using a modified version of Fried frailty criteria. | Healthy volunteers: day 1, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84. | |
Secondary | Physical function | The change in physical function (e.g., gait speed, hand grip strength, chair stand test, balance). | Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84. | |
Secondary | Cognitive function (Montreal Cogntive Assessment) | The change in cognitive function assessed using the MoCA score (0-30 with higher scores representing better cognitive function). | Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84. | |
Secondary | Cognitive function (Digit Symbol Substitution Test) | The change in cognitive function assessed using the Digit Symbol Substitution Test (number of correct symbols). | Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84. | |
Secondary | Quality of life | The change in quality of life assessed using the EuroQol-5D-5L (index value and VAS scale 0-100; with higher scores representing better quality of life). | Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84. | |
Secondary | Self-rated health | The change in self-rated health (score 1-5; 1:"excellent", 2:"very good", 3:"good", 4:"fair", or 5:"bad"). | Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84. |
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