Clinical trial NCT06431932: Pilot Trial of Fisetin in Healthy Volunteers and Older Patients With Multimorbidity
Official title: Pharmacokinetics, Safety, and Efficacy of Fisetin - A Phase I and Pilot Phase IIa Study
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Multimorbidity
Healthy
Keywords: Senolytic
Pharmacokinetics
Chronic inflammation
Lead sponsor: Hvidovre University Hospital
Sponsor class: OTHER
Collaborators: name: University of Southern Denmark
name: Mayo Clinic
First posted: 2024-05-29
Enrollment: 60
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The trial consists of:

* a single-arm open-label study, in which healthy volunteers (n=20) will receive fisetin corresponding to 20 mg/kg/day for two consecutive days.
* a 2-arm triple-blind randomized placebo-controlled study, in which older patients with multimorbidity (n=40) will receive either:

  * 20 mg/kg/day fisetin for two consecutive days, or
  * placebo for two consecutive days.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: The goal of this pilot trial is to conduct a controlled clinical study to gather data on the pharmacokinetic profile of fisetin and its metabolites and on the safety and tolerability of fisetin in healthy volunteers as well as in older medical patients. Furthermore, we aim to identify potential outcome measures and perform sample size calculations for these outcomes, with the intent to conduct a larger scale effect study, at later date, given the result from this pilot study suggests that this would be feasible and safe.

The trial consists of:

* a single-arm open-label study, in which healthy volunteers (n=20) will receive fisetin corresponding to 20 mg/kg/day for two consecutive days.
* a 2-arm triple-blind randomized placebo-controlled study, in which older medical patients (n=40) will receive either:

  * 20 mg/kg/day fisetin for two consecutive days, or
  * placebo for two consecutive days.

Each of the studies (open-label study and randomized placebo-controlled study) consists of three sub-studies:

* Sub-study I aims to investigate the pharmacokinetic properties of fisetin and its main metabolites following oral administration at a dose of 20 mg/kg/day in healthy volunteers and in older medical patients.
* Sub-study II aims to assess the safety and tolerability of oral treatment with fisetin at a dose of 20 mg/kg/day fisetin for two consecutive days in healthy volunteers and in older medical patients.
* Sub-study III aims to gather representative measurements to assess the utility of inflammation, SASP, senescence, senolysis, and aging biomarkers, as well as measures of frailty, clinical parameters, physical and cognitive function, and quality of life as potential outcomes in future clinical trials; additionally, to perform sample size calculations for future trials based on these data.

Eligibility criteria: 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

Primary outcomes:
measure: Population-based pharmacokinetic model for fisetin and metabolites
timeFrame: 24 hours
measure: Adverse events
timeFrame: Day 1 to 3
measure: suPAR
timeFrame: Day 1 to 29
Secondary outcomes:
measure: Population-based PKPD model for fisetin
timeFrame: 24 hours
measure: Renal excretion of fisetin and its main metabolites
timeFrame: 24 hours
measure: Symptoms and adverse events
timeFrame: Day 1 to 3
measure: SASP factors and inflammation markers
timeFrame: Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.
measure: Senescence
timeFrame: Healthy volunteers: day 1, 29. Older patients: day 1, 8, 15, 29, 84.
measure: Senolysis
timeFrame: Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 84.
measure: Aging markers
timeFrame: Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.
measure: Clinical markers
timeFrame: Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.
measure: Frailty Index OutRef
timeFrame: Healthy volunteers: day 1, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.
measure: Frailty Index
timeFrame: Healthy volunteers: day 1, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.
measure: Physical function
timeFrame: Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.
measure: Cognitive function (Montreal Cogntive Assessment)
timeFrame: Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.
measure: Cognitive function (Digit Symbol Substitution Test)
timeFrame: Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.
measure: Quality of life
timeFrame: Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.
measure: Self-rated health
timeFrame: Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.
Other outcomes:
Locations:
Study officials:
affiliation: Copenhagen University Hospital, Amager and Hvidovre
name: Juliette Tavenier
role: STUDY_CHAIR
affiliation: Copenhagen University Hospital, Amager and Hvidovre
name: Line Jee Hartmann Rasmussen
role: STUDY_CHAIR
affiliation: Copenhagen University Hospital, Amager and Hvidovre
name: Morten B Houlind
role: STUDY_CHAIR
affiliation: Copenhagen University Hospital, Amager and Hvidovre
name: Ove Andersen
role: PRINCIPAL_INVESTIGATOR
affiliation: Copenhagen University Hospital, Amager and Hvidovre
name: Jan O Nehlin
role: STUDY_CHAIR
References: