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

Osteoarthritis, Knee Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04210986
• Other study ID #: 2019-16
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 6, 2020
• Est. completion date: February 1, 2023

Study information

• Verified date: December 2023
• Source: Steadman Philippon Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase I/II randomized, double-blind, placebo-controlled clinical trial to test the safety and efficacy of Fisetin for treating mild to moderate osteoarthritis

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 75
• Est. completion date: February 1, 2023
• Est. primary completion date: January 5, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Osteoarthritis
• Osteoarthritis, Knee

Intervention

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.

Drug:
• Placebo oral capsule
Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.

Locations

Country	Name	City	State
United States	The Steadman Clinic	Vail	Colorado

Sponsors (3)

Lead Sponsor	Collaborator
Steadman Philippon Research Institute	Office of Naval Research (ONR), United States Department of Defense

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Treatment-Emergent Adverse Events	Occurrence of adverse events	Duration of study, an average of 12 months
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Change in physical function of the Study Knee (LEK)	Lower Extremity Kinematics	Baseline, 6 months, and 12 months (post 1st drug dose)
Secondary	Change in physical function of the Study Knee (Chair Test)	Stair-Climbing Test	Baseline, 6 months, and 12 months (post 1st drug dose)
Secondary	Change in muscle strength (Isokinetic Dynamometry)	Isokinetic Dynamometry	Baseline, 6 months, and 12 months (post 1st drug dose)
Secondary	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
Secondary	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
Secondary	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)
Secondary	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.