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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04770064
Recruitment Status : Withdrawn (Funding was not awarded)
First Posted : February 25, 2021
Last Update Posted : July 29, 2022
Sponsor:
Collaborator:
Brigham and Women's Hospital
Information provided by (Responsible Party):
Austin V Stone, University of Kentucky

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.

Condition or disease Intervention/treatment Phase
Osteoarthritis, Knee Drug: High-dose/short-duration Fisetin Drug: Low-dose/sustained-duration Fisetin Other: Oral placebo capsule Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Targeting Senescence to Reduce Osteoarthritis Pain and cartilagE Breakdown (ROPE)
Estimated Study Start Date : June 2023
Estimated Primary Completion Date : May 31, 2024
Estimated Study Completion Date : May 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis

Arm Intervention/treatment
Experimental: High-dose/short-duration Fisetin (FIS-hi) Drug: 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.

Experimental: Low-dose/sustained duration Fisetin (FIS-lo) 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.

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




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.


Secondary Outcome Measures :
  1. Pain Visual Analogue Scale (VAS) [ Time Frame: Change between baseline and 3-month follow-up ]
    The Pain VAS is a 100 mm scale where participants will be asked to report their level of pain over the past 24 hours, with 0 being associated with no pain and 100 mm being associated with the worst pain imaginable.

  2. Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) [ Time Frame: Change between baseline and 3-month follow-up ]
    The WOMAC is a 24-item instrument that has been found to be valid and responsive when quantifying changes in pain and function in individuals with knee osteoarthritis. Scores range from 0 to 96 with higher WOMAC scores being associated with worse pain, stiffness, and functional limitations.

  3. Five times sit-to-stand test [ Time Frame: Change between baseline and 3-month follow-up ]
    The five-repetition sit-to-stand is commonly used to measure mobility and function in older adults. Participants are positioned in a standard 16" office chair with their arms at their sides and back located against the back of the chair. Participants are instructed to "Please stand up straight as quickly as you can 5 times, without stopping in between. Keep your arms folded across your chest. I'll be timing you with a stopwatch. Ready, begin." The test is timed using a stopwatch and the timer is stopped when the individual achieves a standing position on the 5th trial. Faster times are associated with less functional impairment.

  4. Biomarker of cellular senescence (MMP-3) [ Time Frame: Change between baseline and 3-month follow-up ]
    Matrix metalloproteinase-3 (MMP-3) is commonly associated with senescence-associated secretory phenotype, and have been previously used to assess the mechanism of action of fisetin in human clinical trials. Greater serum concentrations of MMP-3 are associated with increased senescent cell activity.

  5. Biomarker of cartilage breakdown (CTXII) [ Time Frame: Change between baseline and 3-month follow-up ]
    C-terminal crosslinked telopeptide type II collagen (CTXII) has been identified as a biomarker for the diagnosis, staging, and evaluating the prognosis of hip and knee osteoarthritis, and has also been demonstrated to be responsive over short testing periods (3 months). Greater concentrations are associated with increased cartilage breakdown. CTXII will be measured in the urine and will be normalized to creatinine levels.


Other Outcome Measures:
  1. Need for rescue treatment [ Time Frame: 3-month follow-up ]
    We will record the prevalence and time to rescue intra-articular injections such as a corticosteroid injection.

  2. Treatment Adherence [ Time Frame: 3-month follow-up ]
    Participants will be asked to complete an adherence questionnaire weekly throughout the study period. Participants will be contacted via their preferred method (phone, email, SMS text message). Previous literature has defined good medication compliance as taking at least 80% of the prescribed medication. We will calculate the proportion of patients who meet this criterion in the treatment group as well as the 95% confidence interval (CI) around this compliance rate. The treatments will be considered feasible and acceptable if over 70% of participants reach this threshold.



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Ages Eligible for Study:   35 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04770064


Locations
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United States, Kentucky
UK Healthcare at Turfland
Lexington, Kentucky, United States, 40504
UK HealthCare Joint Reconstruction and Replacement
Lexington, Kentucky, United States, 40508
Sponsors and Collaborators
Austin V Stone
Brigham and Women's Hospital
Investigators
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Principal Investigator: Austin Stone, MD, PhD University of Kentucky
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Responsible Party: Austin V Stone, Assistant Professor, University of Kentucky
ClinicalTrials.gov Identifier: NCT04770064    
Other Study ID Numbers: 65448
First Posted: February 25, 2021    Key Record Dates
Last Update Posted: July 29, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data (IDP) will not be made available to other researchers.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Austin V Stone, University of Kentucky:
Knee
Osteoarthritis
Pain
Inflammation
Additional relevant MeSH terms:
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Osteoarthritis
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases