Senolytic Agent Improve the Benefit of Platelet-Rich Plasma and Losartan

The Use of Senolytic Agent to Improve the Benefit of Platelet-Rich Plasma and Losartan for Treatment of Femoroacetabular Impingement and Labral Tear: A Pilot Study

The purpose is to explore the possible benefit of administration of Fisetin, (a senolytic agent) to improve the benefit of Platelet-Rich Plasma and losartan for treatment of femoroacetabular impingement and labral tear.

We believe that giving Fisetin, a senolytic agent, will improve the benefit of PRP by eliminating senescent cells and senescence-associated secretory phenotype (SASP), known to exist in PRP. The main objectives of this study are to determine if pre- and post-operative administration of a senolytic agent will improve the beneficial effects of PRP when used in conjunction with surgical treatment of FAI and/or labral tear, to determine whether pre- and postoperative administration of Fisetin is associated with adverse events, and to determine if pre- and post-operative administration of Fisetin leads to a decrease in systemic senescence, serum SASP, and fibrotic markers.

Patients suffering from femoroacetabular impingement and labral tear, who are planning to undergo hip arthroscopy combined with standard of care intra-operative PRP injection and post-operative losartan administration will be recruited from the clinical practice of the Principal Clinical Investigator or his designee at The Steadman Clinic (TSC).

Study Overview

• Status: Active, not recruiting
• Conditions: Femoroacetabular Impingement
• Intervention / Treatment: Drug: Fisetin; Drug: Placebo

Detailed Description

This is a pilot, prospective, randomized, double-blind, placebo control clinical trial is proposed to evaluate the safety and efficacy of a senolytic agent (Fisetin) to improve the benefits of standard of care platelet rich plasma (PRP) injection and antifibrotic medication (Losartan) in patients undergoing hip arthroscopy for treatment of femoroacetabular impingement (FAI) and/or labral tear (LT).

• Study Type: Interventional
• Enrollment (Estimated): 68
• 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: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Capacity to personally give informed consent (consent via legally authorized representative will not be accepted) and who are willing to comply with all study-related procedures and assessments
• Between 18 and 80 years of age
• Have been diagnosed with femoroacetabular impingement (FAI) and/or a hip labral tear
• You are scheduled to undergo hip arthroscopy to treat FAI and /or a hip labral tear

Exclusion Criteria:

• Previous or Planned Hip Surgeries, Procedures and/or Treatments:
• Planned surgery on either the contralateral or target hip at any time during the Study period including dosing and follow-up
• Require microfracture on the target hip as part of the planned arthroscopy
• Within 6 months of signing informed consent, has undergone regenerative hip joint procedures on the target hip including, but not limited to, platelet-rich plasma injections, mesenchymal stem cell transplantation
• Have had previous surgery (including microfracture) or diagnostic arthroscopy on the target hip
• Joint space less than ≤2mm
• Tönnis Grade 2-3
• Have a history of pigmented villonodular synovitis (joint disease characterized by inflammation and overgrowth of the synovial lining of the hip joint)
• Have a history of synovial chondromatosis (noncancerous tumor that develops in the synovial lining of the hip joint);
• Have a history of hip dysplasia requiring PAO
• History of Avascular Necrosis (AVN), Perthes disease, or slipped capital femoral epiphysis (SCFE)
• Any active known or suspected systemic autoimmune disease (except for vitiligo, residual auto-immune hypothyroidism requiring hormone replacement only, psoriasis not requiring systemic treatment for two years, conditions not expected to recur in the absence of an external trigger) or any history of a systemic inflammatory arthritis such as psoriatic, rheumatoid, ankylosing spondylitis or reactive arthritis
• Current diagnosis of fibromyalgia based on ACR criteria
• Are unable to or are unwilling to receive a PRP injection as part of your surgery
• Inadequate amount of PRP collected to serve the needs of the patient, and/or ProofPoint Biologics
• Within 2 years of signing informed consent, history of active blood clotting disorders requiring preventative treatment, or active malignancy of any type or history of a malignancy (with the exception of subjects with a history of treated basal or squamous cell carcinoma)
• Baseline HbA1C greater than 6.5, uncontrolled diabetes mellitus, and/or medication management has not been stable in the previous 2 months
• Current or prior history of other joint diseases that may (in the opinion of the Principal Clinical Investigator or his/her designee) confound study data or increase Subject risk. These may include including but not limited to joint dysplasia, crystal-induced arthropathy (such as gout, or calcium pyrophosphate deposition disease evidenced by clinical and/or radiographic means), aseptic osteonecrosis, acromegaly, Paget's disease, Ehlers-Danlos Syndrome, Gaucher's disease, Stickler syndrome, joint infection, hemochromatosis, or neuropathic arthropathy of any cause
• Any medical condition, including findings in laboratory or medical history or in the baseline assessments, that (in the opinion of the Principal Clinical Investigator or his/her designee), constitutes a risk or contraindication for participation in the Study or that could interfere with the Study conduct, endpoint evaluation or prevent the subject from fully participating in all aspects of the Study
• Females who are nursing a child, are pregnant, or who are planning to become pregnant during study drug dosing, or who are not willing to abstain from sex without the use of contraceptive protection during study drug dosing
• Males who do not wish to abstain from sex with women of childbearing potential without use of contraceptive protection during study drug dosing
• Currently taking warfarin or any drug that could cause a coagulopathy event
• Within 1 week of signing informed consent. taking medications that affect insulin activity, including Metformin or Acarbose
• Have an allergy to any active or inactive ingredient of Losartan or Fisetin, and/or currently taking medication with known adverse Losartan or Fisetin interaction
• Within 3 months of signing informed consent have taken senolytic agents including: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax;
• Currently taking the following drugs if they cannot be held for at least 2 days (per enrolling Principal Investigator or Sub Investigator, or healthcare professional appropriately delegated by the Principal Investigator) before and during administration of Fisetin: cyclosporine, tacrolimus, repaglinide, and bosentan
• Currently taking drugs that induce cellular senescence, including alkylating agents, anthracyclines, platins, other chemotherapy
• Within 1 month of signing informed consent, taking a glucocorticoid
• Has current history of drug and/or alcohol abuse
• Within the 3 months of signing informed consent has received anticonvulsant therapy, pharmacological doses of thyroid hormone (causing decline of thyroid stimulating hormone below normal)
• Within the 12 months prior to signing informed consent received any medications that affect bone turnover, including: adrenocorticosteroids (> 3 months at any time or > 10 days, estrogen (E) therapy or treatment with a selective E receptor modulator, or teriparatide
• Inability to tolerate oral medication.

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 group (investigational group); 20mg/kg of Fisetin per day for days 1 and 2 prior to surgery and days 33, 34, 63, 64, 93, and 94 post surgery. (The pills are 100mg each. For example, if a participant weighs 160 pounds (about 73 kg), the participant will need to take 15 pills per day)	Drug: Fisetin; Oral Fisetin 20 mg/kg taken for 8 days total.; Other Names: 3,3',4',7-tetrahydroxyflavone; Novusetin; 7,3',4'-flavon-3-ol
Placebo Comparator: Placebo group (control group); 20mg/kg of Placebo per day for days 1 and 2 prior to surgery and days 33, 34, 63, 64, 93, and 94 post surgery. (The pills are 100mg each. For example, if a participant weighs 160 pounds (about 73 kg), the participant will need to take 15 pills per day)	Drug: Placebo; Fisetin appearance-matched microcrystalline cellulose placebo. 20 mg/kg taken for 8 days total.; Other Names: Placebo Oral Capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events	Occurrence of adverse events	From date of study drug dosing until the end of the study, an average of 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Reported Outcomes Questionnaire-Modified Harris Hip Score (mHHS)	Consists of 8 questions covering domains of pain, gait, and functional activities. Scored on a 100-point scale, with each answer receiving a specific amount of points. Higher score represents greater hip health.	Baseline, 8-12 weeks post-op, 6 months post-op, and 12 months post-op
Patient Reported Outcomes Questionnaire- Hip Outcome Score: activities of daily living and sports subscales (HOS-ADL, HOS-SSS)	Includes two subscales to calculate the total score:19 items in the HOS-ADL subscale and 9 items in the HOS-sports subscale.	Baseline, 8-12 weeks post-op, 6 months post-op, and 12 months post-op
Patient Reported Outcomes Questionnaire-Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)	Scale from 0-96. Higher score represents worse hip health.	Baseline, 8-12 weeks post-op, 6 months post-op, and 12 months post-op
Patient Reported Outcomes Questionnaire-Optum Short Form physical and mental component scores (SF-12 PCS and SF-12 MCS)	Includes two subscales to calculate the total score. Higher score represents greater health. Scale standardized to a US Population mean of 50 and standard deviation of 10 points.	Baseline, 8-12 weeks post-op, 6 months post-op, and 12 months post-op
Patient Reported Outcomes Questionnaire-Tegner Activity Scale	Scale from 0-10. Higher score represents greater activity level.	Baseline, 8-12 weeks post-op, 6 months post-op, and 12 months post-op
Patient Reported Outcomes Questionnaire-Numeric Rating Scale for Hip Pain	Scale from 1-10. Higher score represents greater hip pain.	Baseline, 8-12 weeks post-op, 6 months post-op, and 12 months post-op
Patient Reported Outcomes Questionnaire-Patient satisfaction with surgical outcome	1-10-point scale	Baseline, 8-12 weeks post-op, 6 months post-op, and 12 months post-op
Multi and singleplex immunoassays and flow cytometry senescence and SASP marker assessment of peripheral blood	Concentrations of secreted protein markers found in serum in pg/ml	Baseline, and 8-12 weeks post-op
Incidence of revision arthroscopy or other hip surgery required post initial arthroscopy	Incidence of revision surgery from day of initial surgery will be recorded	From day of initial surgery until the end of the study, an average of 12 months

Collaborators and Investigators

• Sponsor: Steadman Philippon Research Institute
• Collaborators: United States Department of Defense
• Investigators: Principal Investigator: Johnny L Huard, PhD, Steadman Philippon Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2021
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): October 31, 2024

Study Registration Dates

• First Submitted: August 2, 2021
• First Submitted That Met QC Criteria: August 24, 2021
• First Posted (Actual): August 30, 2021

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: FAI Labral tear Fisetin Losartan
• Additional Relevant MeSH Terms: Pathologic Processes; Joint Diseases; Musculoskeletal Diseases; Femoracetabular Impingement
• Other Study ID Numbers: 2020-058

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