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

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ClinicalTrials.gov Identifier: NCT04210986
Recruitment Status : Recruiting
First Posted : December 26, 2019
Last Update Posted : December 3, 2020
Sponsor:
Collaborators:
United States Department of Defense
Office of Naval Research (ONR)
Information provided by (Responsible Party):
Steadman Philippon Research Institute

Brief 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

Condition or disease Intervention/treatment Phase
Osteoarthritis, Knee Dietary Supplement: Fisetin Drug: Placebo oral capsule Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial
Actual Study Start Date : January 6, 2020
Estimated Primary Completion Date : December 1, 2022
Estimated Study Completion Date : December 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis

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:
  • Novusetin
  • 7,3',4'-flavon-3-ol
  • 3,3',4',7-tetrahydroxyflavone

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.




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events as assessed by blood chemistries (Liver) [ Time Frame: Duration of study, an average of 12 months ]
    Evaluation of liver toxicity by measuring peripheral blood chemistry (CMP)

  2. Incidence of Treatment-Emergent Adverse Events as assessed by blood chemistries (Kidney) [ Time Frame: Duration of study, an average of 12 months ]
    Evaluation of kidney toxicity by measuring peripheral blood chemistry (CMP & Creatine Kinase)

  3. Incidence of Treatment-Emergent Adverse Events as assessed by blood chemistries (Lysis Syndrome) [ Time Frame: Duration of study, an average of 12 months ]
    Evaluation of Tumor Lysis Syndrome by measuring peripheral blood chemistry (CMP & Uric acid)


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. Change in physical function of the Study Knee (LEK) [ Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose) ]
    Lower Extremity Kinematics

  7. 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

  8. Change in muscle strength (Isokinetic Dynamometry) [ Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose) ]
    Isokinetic Dynamometry

  9. 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

  10. 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

  11. 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

  12. 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.



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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04210986


Contacts
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Contact: Suzanne L Page, JD 970-401-8770 spage@sprivail.org
Contact: Mike Begg, PA 970-401-8755 mbegg@sprivail.org

Locations
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United States, Colorado
The Steadman Clinic Recruiting
Vail, Colorado, United States, 81657
Principal Investigator: Thomas A Evans, MD         
Sub-Investigator: Raymond Kim, MD         
Sponsors and Collaborators
Steadman Philippon Research Institute
United States Department of Defense
Office of Naval Research (ONR)
Investigators
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Principal Investigator: Thomas A Evans, MD The Steadman Clinic
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Responsible Party: Steadman Philippon Research Institute
ClinicalTrials.gov Identifier: NCT04210986    
Other Study ID Numbers: 2019-16
First Posted: December 26, 2019    Key Record Dates
Last Update Posted: December 3, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Steadman Philippon Research Institute:
Fisetin
Inflammation
Osteoarthritis
Additional relevant MeSH terms:
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Osteoarthritis
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases