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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 : Active, not recruiting
First Posted : December 26, 2019
Last Update Posted : July 6, 2021
Sponsor:
Collaborators:
United States Department of Defense
Office of Naval Research (ONR)
Information provided by (Responsible Party):
Steadman Philippon Research Institute

Tracking Information
First Submitted Date  ICMJE December 3, 2019
First Posted Date  ICMJE December 26, 2019
Last Update Posted Date July 6, 2021
Actual Study Start Date  ICMJE January 6, 2020
Estimated Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 26, 2020)
  • 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)
  • 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)
  • 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)
Original Primary Outcome Measures  ICMJE
 (submitted: December 20, 2019)
  • Incidence of Treatment-Emergent Adverse Events as assessed by blood chemistries (Liver) [ Time Frame: Duration of study, an average of 18 months ]
    Evaluation of liver toxicity by measuring peripheral blood chemistry (CMP)
  • Incidence of Treatment-Emergent Adverse Events as assessed by blood chemistries (Kidney) [ Time Frame: Duration of study, an average of 18 months ]
    Evaluation of kidney toxicity by measuring peripheral blood chemistry (CMP & Creatine Kinase)
  • Incidence of Treatment-Emergent Adverse Events as assessed by blood chemistries (Lysis Syndrome) [ Time Frame: Duration of study, an average of 18 months ]
    Evaluation of Tumor Lysis Syndrome by measuring peripheral blood chemistry (CMP & Uric acid)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 26, 2020)
  • 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
  • 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
  • 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
  • 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
  • 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
  • Change in physical function of the Study Knee (LEK) [ Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose) ]
    Lower Extremity Kinematics
  • 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
  • Change in muscle strength (Isokinetic Dynamometry) [ Time Frame: Baseline, 6 months, and 12 months (post 1st drug dose) ]
    Isokinetic Dynamometry
  • 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
  • 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
  • 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
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2019)
  • Change in levels of pro-inflammatory markers associated with Senescence [ Time Frame: Baseline, 14 days, 45 days, 6 months, 18 months (post 1st drug dose) ]
    Detection of inflammatory markers in peripheral blood using multiplex protein analyte analysis
  • Change in levels of cartilage degenerating markers associated with OA [ Time Frame: Baseline, 14 days, 45 days, 6 months, 18 months (post 1st drug dose) ]
    Detection of cartilage degenerating markers in peripheral blood using multiplex protein analyte analysis
  • Change in physical function of the Study Knee (6 min walk) [ Time Frame: Baseline, 6 months, and 18 months (post 1st drug dose) ]
    6-min walk test
  • Change in physical function of the Study Knee (timed-up-and-go test) [ Time Frame: Baseline, 6 months, and 18 months (post 1st drug dose) ]
    timed-up-and-go test
  • Change in physical function of the Study Knee (fast 4-meter walk) [ Time Frame: Baseline, 6 months, and 18 months (post 1st drug dose) ]
    fast 4-meter walk test
  • Change in physical function of the Study Knee (LEK) [ Time Frame: Baseline, 6 months, and 18 months (post 1st drug dose) ]
    Lower Extremity Kinematics
  • Change in physical function of the Study Knee (Chair Test) [ Time Frame: Baseline, 6 months, and 18 months (post 1st drug dose) ]
    Stair-Climbing Test
  • Change in muscle strength (Isokinetic Dynamometry) [ Time Frame: Baseline, 6 months, and 18 months (post 1st drug dose) ]
    Isokinetic Dynamometry
  • 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 and 18 months ]
    NRS pain scale
  • 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 and 18 months ]
    IKDC, WOMAC, Tegner activity scale and Lysholm
  • Change in the quality of articular cartilage in the Study Knee with quantitative magnetic resonance imaging (MRI) [ Time Frame: Baseline, 6 months, and 18 months (post 1st drug dose) ]
    Quantitative MRI using T2 and/or T2* mapping images
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial
Official Title  ICMJE Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial
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
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Osteoarthritis, Knee
Intervention  ICMJE
  • 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
  • Drug: Placebo oral capsule
    Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Study Arms  ICMJE
  • 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)
    Intervention: Dietary Supplement: Fisetin
  • 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)
    Intervention: Drug: Placebo oral capsule
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: July 2, 2021)
100
Original Estimated Enrollment  ICMJE
 (submitted: December 20, 2019)
72
Estimated Study Completion Date  ICMJE December 1, 2022
Estimated Primary Completion Date December 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04210986
Other Study ID Numbers  ICMJE 2019-16
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Steadman Philippon Research Institute
Study Sponsor  ICMJE Steadman Philippon Research Institute
Collaborators  ICMJE
  • United States Department of Defense
  • Office of Naval Research (ONR)
Investigators  ICMJE
Principal Investigator: Thomas A Evans, MD The Steadman Clinic
PRS Account Steadman Philippon Research Institute
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP