Pilot Trial of Fisetin in Healthy Volunteers and Older Patients With Multimorbidity

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 atrisk or would preclude the participant from successfully completing all aspects ofthe 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 theinvestigator believes would put the subject at risk or would preclude the patientfrom 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 clinicaljudgment (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 oras per clinical judgment

• Subjects taking specified inhibitors, inducers, or substrates of CYP2D6, CYP2C9, orCYP2C8, or as per clinical judgment

• Subjects regularly using drug classes or specific medications or as per clinicaljudgment

• Use of senolytic and other "anti-aging" supplements