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

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: Completed
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Dietary supplement: Fisetin; Drug: Placebo oral capsule

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: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Occurrence of adverse events	Duration of study, an average of 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in levels of pro-inflammatory markers associated with Senescence	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	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)	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)	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)	fast 40-meter walk test	Baseline, 6 months, and 12 months (post 1st drug dose)
Change in physical function of the Study Knee (LEK)	Lower Extremity Kinematics	Baseline, 6 months, and 12 months (post 1st drug dose)
Change in physical function of the Study Knee (Chair Test)	Stair-Climbing Test	Baseline, 6 months, and 12 months (post 1st drug dose)
Change in muscle strength (Isokinetic Dynamometry)	Isokinetic Dynamometry	Baseline, 6 months, and 12 months (post 1st drug dose)
Evaluation of patient reported outcomes (PROs) for knee pain	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	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)	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	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

• Sponsor: Steadman Philippon Research Institute
• Collaborators: United States Department of Defense; Office of Naval Research (ONR)
• Investigators: Principal Investigator: Thomas A Evans, MD, The Steadman Clinic

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2020
• Primary Completion (Actual): January 5, 2023
• Study Completion (Actual): February 1, 2023

Study Registration Dates

• First Submitted: December 3, 2019
• First Submitted That Met QC Criteria: December 20, 2019
• First Posted (Actual): December 26, 2019

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: December 29, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Inflammation; Osteoarthritis; Fisetin
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID 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