Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial

December 29, 2023 updated by: Steadman Philippon Research Institute
Phase I/II randomized, double-blind, placebo-controlled clinical trial to test the safety and efficacy of Fisetin for treating mild to moderate osteoarthritis

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This is a Phase I/II randomized, double-blind, placebo-controlled clinical trial that will be conducted at The Steadman Clinic (TSC) and Steadman Philippon Research Institute (SPRI). The purpose of this study is to evaluate the clinical efficacy of Fisetin (FIS), a dietary supplement, in symptomatic knee osteoarthritis (OA) patients. Key aspects of this proposal include the investigator's well-developed methodologies to measure and compare systemic senescence-associated secretory phenotype (SASP) including inflammatory biomarkers and senescent cells, and collect magnetic resonance images, self-reported outcomes, physical performance and other objective clinical data. Given the drug FIS has been empirically demonstrated to reduce senescent cell burden, the main objective(s) are to determine 1) the safety of FIS during dosing and 2) whether FIS reduces senescent cells, pro-inflammatory and cartilage degenerating SASP markers, and reduces OA-symptoms leading to improved joint health and function.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
75

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Vail, Colorado, United States, 81657
        • The Steadman Clinic

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

40 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Subjects will be included if all the following criteria are met:

  1. Are male or female, ages 40-80;
  2. Are willing to comply with all study related procedures and assessments;
  3. Are ambulatory as defined by ability to complete functional performance testing;
  4. Radiographic evidence of Kellgren-Lawrence grade II-IV osteoarthritis in one or both knees;
  5. Scores 4-10 on the Numerical Rating Scale (NRS) for pain;
  6. Stable dose of screening/baseline medications for at least 2 months prior to the anticipated date of study drug dosing.

Exclusion Criteria:

Subjects will be excluded if any of the following criteria are met:

  1. Females who are nursing, pregnant or planning to become pregnant during the duration of study drug dosing;
  2. Males who do not wish to abstain from sex or use contraceptive protection during study drug dosing and for 2 weeks after the last dose;
  3. Subjects who do not have the capacity to consent themselves;
  4. Subjects who are unable to tolerate oral medication;

  5. Subjects having previously undergone any of the following treatments in the stated time window.

    • Surgery on the Study Knee in the past 6 months;
    • Partial or complete joint replacement in the study knee. Partial or complete joint replacement in the contralateral knee is acceptable as long as the surgery was performed at least 6 months prior to enrollment and the operative knee is asymptomatic;
    • Patients who have undergone arthroscopic surgery (including microfracture and meniscectomy) on the Study Knee in the last 2 years prior to the Screening visit or are anticipated to have arthroscopic surgery on either knee at any time during the study period;
    • Steroid injection, including extended-release corticosteroid (e.g., Zilretta®) within the last 5 months;
    • Biologic (platelet-rich plasma, bone marrow, adipose tissue/cells) or hyaluronic acid injection into the Study Knee in the past 6 months;

  6. Subjects with any of the following drug/medication statuses:

    • Currently taking Losartan;
    • Currently taking Warfarin or related anticoagulants;
    • Opioid analgesics taken in the past 8 weeks and are not willing to discontinue these medications through the duration of the study;
    • Senolytic agents taken within the past 6 months and are not willing to discontinue these medications through the duration of the study, including: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax;
    • Drugs that induce significant cellular stress and are not willing to discontinue these medications through the duration of the study, including alkylating agents, anthracyclines, platins, other chemotherapy drugs;
    • Subjects taking the following other drugs if they cannot be held (per the Principal Investigator) for at least 2 days before and during administration of Fisetin: cyclosporine, tacrolimus, repaglinide, and bosentan.

  7. Subjects with any of the following disease statuses:

    • Significant liver disease (i.e. greater than or equal to 2x the upper limit of normal bilirubin levels) or as in the opinion of the Principal Investigator;
    • Significant renal disease (eGFR of <60 ml/min/1.73m2) or as in the opinion of the Principal Investigator;
    • History of other formally diagnosed joint diseases including osteonecrosis, acromegaly, Paget's disease, Ehlers-Danlos Syndrome, Gaucher's disease, Cushing's syndrome, Stickler's syndrome, joint infection, hemophilia, hemochromatosis, or neuropathic arthropathy of any cause;
    • Any active systemic autoimmune disease with musculoskeletal involvement or any history of system inflammatory arthritis;
    • Patients with type 1 or 2 diabetes (HbA1c>6.5%) and/or taking medications that affect insulin levels, including: Metformin (within the last week), Glucocorticoids (within the last month), Acarbose (within the last week);
  8. Subjects unable to safely practically undergo an MRI (BMI > 40 kg/m2) or size exceeding limits of MRI equipment, implanted metal in study knee near joint surface, incompatible implant/device, severe claustrophobia;
  9. Subjects that have any medical condition, including laboratory findings and findings in the medical history or in the pre-study assessments, that in the opinion of the Investigator constitutes a risk or contraindication for participation in the study or that could interfere with the study objectives, conduct or evaluation or prevent the patient from fully participating in all aspects of the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Fisetin
Fisetin 100 mg capsules (~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32)
Dietary supplement: Fisetin
Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Other Names:
  • 3,3',4',7-tetrahydroxyflavone
  • Novusetin
  • 7,3',4'-flavon-3-ol
Placebo Comparator: Placebo
Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32)
Drug: Placebo oral capsule
Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Incidence of Treatment-Emergent Adverse Events
Time Frame: Duration of study, an average of 12 months
Occurrence of adverse events
Duration of study, an average of 12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in levels of pro-inflammatory markers associated with Senescence
Time Frame: Baseline, 14 days, 45 days, 6 months, 12 months (post 1st drug dose)
Detection of inflammatory markers in peripheral blood using multiplex protein analyte analysis
Baseline, 14 days, 45 days, 6 months, 12 months (post 1st drug dose)
Change in levels of cartilage degenerating markers associated with OA
Time Frame: Baseline, 14 days, 45 days, 6 months, 12 months (post 1st drug dose)
Detection of cartilage degenerating markers in peripheral blood using multiplex protein analyte analysis
Baseline, 14 days, 45 days, 6 months, 12 months (post 1st drug dose)
Change in physical function of the Study Knee (6 min walk)
Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose)
6-min walk test
Baseline, 6 months, and 12 months (post 1st drug dose)
Change in physical function of the Study Knee (timed-up-and-go test)
Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose)
timed-up-and-go test
Baseline, 6 months, and 12 months (post 1st drug dose)
Change in physical function of the Study Knee (fast 40-meter walk)
Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose)
fast 40-meter walk test
Baseline, 6 months, and 12 months (post 1st drug dose)
Change in physical function of the Study Knee (LEK)
Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose)
Lower Extremity Kinematics
Baseline, 6 months, and 12 months (post 1st drug dose)
Change in physical function of the Study Knee (Chair Test)
Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose)
Stair-Climbing Test
Baseline, 6 months, and 12 months (post 1st drug dose)
Change in muscle strength (Isokinetic Dynamometry)
Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose)
Isokinetic Dynamometry
Baseline, 6 months, and 12 months (post 1st drug dose)
Evaluation of patient reported outcomes (PROs) for knee pain
Time Frame: Baseline, every 3 days for the first 6-weeks of drug dosing, every week the last 6 weeks of dosing, then 6 months, 12 months, and 18 months
NRS pain scale
Baseline, every 3 days for the first 6-weeks of drug dosing, every week the last 6 weeks of dosing, then 6 months, 12 months, and 18 months
Evaluation of patient reported outcomes (PROs) for knee function
Time Frame: Baseline, every 3 days for the first 6-weeks of drug dosing, every week the last 6 weeks of dosing, then 6 months, 12 months, and 18 months
IKDC, WOMAC, Tegner activity scale and Lysholm
Baseline, every 3 days for the first 6-weeks of drug dosing, every week the last 6 weeks of dosing, then 6 months, 12 months, and 18 months
Change in the quality of articular cartilage in the Study Knee with quantitative magnetic resonance imaging (MRI)
Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose)
Quantitative MRI using T2 and/or T2* mapping images
Baseline, 6 months, and 12 months (post 1st drug dose)
Change in time to conversion to alternative treatment
Time Frame: Patients will be allowed to receive a steroid injection at any point during the 18-month study. The time to resort to this alternative therapy from baseline will be recorded.
Patients will be allowed to receive a steroid injection and still participate in the study. The time to resort to this alternative therapy from baseline will be recorded.
Patients will be allowed to receive a steroid injection at any point during the 18-month study. The time to resort to this alternative therapy from baseline will be recorded.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Steadman Philippon Research Institute

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
United States Department of Defense
Office of Naval Research (ONR)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Thomas A Evans, MD, The Steadman Clinic

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 6, 2020

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 5, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 1, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 3, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 20, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 26, 2019

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 18, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 29, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2019-16

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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