Targeting Senescence to Reduce Osteoarthritis Pain and cartilagE Breakdown (ROPE)
Overview
- Phase
- Phase 1
- Intervention
- High-dose/short-duration Fisetin
- Conditions
- Osteoarthritis, Knee
- Sponsor
- Austin V Stone
- Locations
- 2
- Primary Endpoint
- Change in markers of liver toxicity
- Status
- Withdrawn
- Last Updated
- 3 years ago
Overview
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.
Investigators
Austin V Stone
Assistant Professor
University of Kentucky
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;
Arms & Interventions
High-dose/short-duration Fisetin (FIS-hi)
Intervention: High-dose/short-duration Fisetin
Low-dose/sustained duration Fisetin (FIS-lo)
Intervention: Low-dose/sustained-duration Fisetin
Placebo
Intervention: Oral placebo capsule
Outcomes
Primary Outcomes
Change in markers of liver toxicity
Time Frame: Change between baseline and 3-month follow-up
The change in 2 markers of liver toxicity between baseline and 3-month follow-up will be assessed. Alanine amino transferase (ALT) and aspartate amino transferase (AST) are enzymes found mostly in the cells of the liver and kidney, and heart and liver, respectively. Both are useful tests for detecting liver damage.
Change in markers of tumor lysis syndrome
Time Frame: Change between baseline and 3-month follow-up
Tumor lysis syndrome is characterized by high blood potassium, low blood calcium, and high blood uric acid. The change in potassium, calcium and uric acid between baseline and 3-month follow-up will be assessed.
Change in markers of kidney toxicity
Time Frame: Change between baseline and 3-month follow-up
The change in 2 markers of kidney toxicity between baseline and 3-month follow-up will be assessed. Blood urea nitrogen (BUN) is a waste product filtered out of the blood by the kidneys. As kidney function decreases, the BUN level rises. Creatine kinase (CK) is also an enzyme that is used to assess kidney function. Higher CK values are associated with greater burden on the kidneys.
Secondary Outcomes
- Five times sit-to-stand test(Change between baseline and 3-month follow-up)
- Biomarker of cellular senescence (MMP-3)(Change between baseline and 3-month follow-up)
- Biomarker of cartilage breakdown (CTXII)(Change between baseline and 3-month follow-up)
- Pain Visual Analogue Scale (VAS)(Change between baseline and 3-month follow-up)
- Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC)(Change between baseline and 3-month follow-up)