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

NCT04770064 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 65448
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

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

Keywords

Knee; Osteoarthritis; Pain; Inflammation

Outcome Measures

Primary Outcomes (3)

• Change in markers of liver toxicity

  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 between baseline and 3-month follow-up

• Change in markers of kidney toxicity

  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.

  Change between baseline and 3-month follow-up

• Change in markers of tumor lysis syndrome

  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 between baseline and 3-month follow-up

Secondary Outcomes (5)

• 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

• 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

Other Outcomes (2)

• Need for rescue treatment

  3-month follow-up

• Treatment Adherence

  3-month follow-up

Study Arms (3)

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

EXPERIMENTAL

Drug: High-dose/short-duration Fisetin

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

EXPERIMENTAL

Drug: Low-dose/sustained-duration Fisetin

Placebo

PLACEBO COMPARATOR

Other: Oral placebo capsule

Interventions

High-dose/short-duration Fisetin 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.

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

Low-dose/sustained-duration Fisetin 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.

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

Oral placebo capsule OTHER

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

Placebo

Eligibility Criteria

• Age: 35 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Austin V Stone: lead
• Brigham and Women's Hospital: collaborator

Study Sites (2)

UK Healthcare at Turfland

Lexington, Kentucky, 40504, United States

Location

UK HealthCare Joint Reconstruction and Replacement

Lexington, Kentucky, 40508, United States

Location

MeSH Terms

Conditions

Osteoarthritis, Knee; Osteoarthritis; Pain; Inflammation

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Pathologic Processes

Study Officials

• Austin Stone, MD, PhD

  University of Kentucky

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: February 16, 2021
• First Posted: February 25, 2021
• Study Start: June 1, 2023
• Primary Completion: May 31, 2024
• Study Completion: May 31, 2024
• Last Updated: July 29, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)