Targeting Senescence to Reduce Osteoarthritis Pain and cartilagE Breakdown (ROPE)

NCT ID: NCT04770064

Last Updated: 2022-07-29

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1/PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-30
• Study Completion Date: 2024-05-31

Brief Summary

Symptomatic knee osteoarthritis (OA) is the most common joint disorder in the U.S. and a leading cause of disability. Increasing age, obesity, and previous injury increase the lifetime risk of knee OA, but these factors are also independently associated with increased cellular senescence. Senescent cells accumulate in many tissues and contribute to chronic pathologies, linked to the secretion of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype. In OA, senescent cells promote production of cytokines, chemokines, and matrix-degrading enzymes involved in progressive cartilage breakdown. The senolytic supplement fisetin alters the inflammatory and catabolic cartilage responses, which may clinically lessen OA pain while also slowing progressive cartilage breakdown. The purpose of this double-blind, randomized clinical trial is to compare 2 fisetin dosing regimens versus placebo. Sixty patients with mild to moderate knee OA will be assessed at baseline and 3 months in an effort to: determine if 2 different fisetin dosing regimens lessen pain and functional impairment compared to placebo, compare progressive changes in senescent cell activity and biomarkers of cartilage degradation between different fisetin dosing regimens and placebo, and assess acceptability and feasibility of 2 fisetin dosing regimens.

Conditions

Osteoarthritis, Knee

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

High-dose/short-duration Fisetin (FIS-hi)

Group Type: EXPERIMENTAL

High-dose/short-duration Fisetin

Intervention Type: DRUG

Fisetin is a plant flavanol senolytic found in strawberries, persimmons, and cucumbers. It has senolytic properties that may provide therapeutic benefit for those with knee osteoarthritis. Participants will be asked to take approximately 20 mg/kg of body mass for 2 consecutive days, followed by a 28-day washout period, and then another 2-day administration.

Low-dose/sustained duration Fisetin (FIS-lo)

Group Type: EXPERIMENTAL

Low-dose/sustained-duration Fisetin

Intervention Type: DRUG

Fisetin is a plant flavanol senolytic found in strawberries, persimmons, and cucumbers. It has senolytic properties that may provide therapeutic benefit for those with knee osteoarthritis. Participants will be asked to take one, 100 mg capsule of fisetin daily for 90 days.

Placebo

Group Type: PLACEBO_COMPARATOR

Oral placebo capsule

Intervention Type: OTHER

Participants will be asked to take one, 100 mg oral placebo capsule (corn starch) daily for 90 days.

Interventions

High-dose/short-duration Fisetin

Fisetin is a plant flavanol senolytic found in strawberries, persimmons, and cucumbers. It has senolytic properties that may provide therapeutic benefit for those with knee osteoarthritis. Participants will be asked to take approximately 20 mg/kg of body mass for 2 consecutive days, followed by a 28-day washout period, and then another 2-day administration.

Intervention Type: DRUG

Low-dose/sustained-duration Fisetin

Fisetin is a plant flavanol senolytic found in strawberries, persimmons, and cucumbers. It has senolytic properties that may provide therapeutic benefit for those with knee osteoarthritis. Participants will be asked to take one, 100 mg capsule of fisetin daily for 90 days.

Intervention Type: DRUG

Oral placebo capsule

Participants will be asked to take one, 100 mg oral placebo capsule (corn starch) daily for 90 days.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Are male or female, ages 35-80;
• Are willing to comply with all study related procedures and assessments;
• Are ambulatory as defined by ability to complete functional performance testing;
• Radiographic evidence of Kellgren-Lawrence grade II-IV osteoarthritis in one or both knees;
• Scores between 40 and 80 mm on the pain VAS;
• Stable dose of screening/baseline medications for at least 2 months prior to the anticipated date of study drug dosing.

Exclusion Criteria

• Females who are nursing, pregnant or planning to become pregnant during the duration of study drug dosing;
• 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;
• Subjects who do not have the capacity to consent themselves;
• Subjects who are unable to tolerate oral medication;
• 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;
• Patients that have had a recent intraarticular OA treatment:
• Glucocorticoid injection, within the last 2 months;
• Extended-release corticosteroid, hyaluronic acid, or biologic injection (platelet-rich plasma, bone marrow, adipose tissue/cells) into the Study Knee in the past 6 months;
• 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;
• 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.
• 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);
• Subjects with moderate to severe depression (PHQ-9 score > 10) will also be excluded since knee OA patients with depression have previously demonstrated worse pain trajectories;
• 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.

• Minimum Eligible Age: 35 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: collaborator

Austin V Stone

OTHER

Sponsor Role: lead

Responsible Party

Austin V Stone

Assistant Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Austin Stone, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Kentucky

Locations

UK Healthcare at Turfland

Lexington, Kentucky, United States

UK HealthCare Joint Reconstruction and Replacement

Lexington, Kentucky, United States

Countries

United States

Other Identifiers

65448

Identifier Type: -

Identifier Source: org_study_id