Overview

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

Status:
Not yet recruiting
Trial end date:
2024-05-31
Target enrollment:
0
Participant gender:
All
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.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Austin V Stone
Collaborator:
Brigham and Women's Hospital
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.