Pharmacokinetics, Safety, and Efficacy of Fisetin - A Phase I and Pilot Phase IIa Study
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Population-based pharmacokinetic model for fisetin and metabolites
研究概览
简要总结
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.
详细描述
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:
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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.
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a 2-arm triple-blind randomized placebo-controlled study, in which older medical patients (n=40) will receive either:
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20 mg/kg/day fisetin for two consecutive days, or
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placebo for two consecutive days.
Each of the studies (open-label study and randomized placebo-controlled study) consists of three sub-studies:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Single-arm open-label study in healthy volunteers
Healthy volunteers will receive fisetin.
干预措施: Fisetin (Drug)
RCT - Placebo group
Older patients with multimorbidity will receive placebo.
干预措施: Placebo (Drug)
RCT - Treatment group
Older patients with multimorbidity will receive fisetin.
干预措施: Fisetin (Drug)
结局指标
主要结局
Population-based pharmacokinetic model for fisetin and metabolites
时间窗: 24 hours
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.
Adverse events
时间窗: Day 1 to 3
Number of participants to experience adverse events
suPAR
时间窗: Day 1 to 29
The change in plasma levels of suPAR and a sample size calculation based on these data.
次要结局
- Senescence(Healthy volunteers: day 1, 29. Older patients: day 1, 8, 15, 29, 84.)
- Symptoms and adverse events(Day 1 to 3)
- SASP factors and inflammation markers(Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.)
- Population-based PKPD model for fisetin(24 hours)
- Senolysis(Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 84.)
- Aging markers(Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.)
- Self-rated health(Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.)
- Renal excretion of fisetin and its main metabolites(24 hours)
- Clinical markers(Healthy volunteers: day 1, 2, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.)
- Frailty Index OutRef(Healthy volunteers: day 1, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.)
- Physical function(Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.)
- Frailty Index(Healthy volunteers: day 1, 29. Older patients: day 1, 2, 8, 15, 29, 57, 84.)
- Cognitive function (Montreal Cogntive Assessment)(Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.)
- Cognitive function (Digit Symbol Substitution Test)(Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.)
- Quality of life(Healthy volunteers: day 1, 29. Older patients: day 1, 29, 84.)
研究者
Ove Andersen
Head of Research, Clinical Professor, Principal Investigator
Hvidovre University Hospital