Osteoarthritis, KneePhase 1/2ROPENCT04770064
Targeting Senescence to Reduce Osteoarthritis Pain and cartilagE Breakdown (ROPE)
A Phase 1/2 study testing High-dose/short-duration Fisetin and Low-dose/sustained-duration Fisetin in people with Osteoarthritis, Knee, run by Austin V Stone at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 35 to 80 years
- Conditions the study is for
- Osteoarthritis, Knee
- What is being tested?
- High-dose/short-duration Fisetin and Low-dose/sustained-duration Fisetin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 2 sitesUnited States
- Study dates
- Jun 2023to 31 May 2024
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
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- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
UK Healthcare at Turfland
Lexington, Kentucky, 40504
UK HealthCare Joint Reconstruction and Replacement
Lexington, Kentucky, 40508
About this study
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
- Being tested
- High-dose/short-duration Fisetin, Low-dose/sustained-duration Fisetin, Oral placebo capsule
- Keywords
- Knee, Osteoarthritis, Pain, Inflammation
- Medical subject headings
- Osteoarthritis, Knee, Osteoarthritis, Pain, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High-dose/short-duration FisetinDrug
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 FisetinDrug
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.
Oral placebo capsuleOther
Participants will be asked to take one, 100 mg oral placebo capsule (corn starch) daily for 90 days.
| Study group | Role | What they receive |
|---|---|---|
| High-dose/short-duration Fisetin (FIS-hi) | Experimental | Not described Receives: Drug: High-dose/short-duration Fisetin |
| Low-dose/sustained duration Fisetin (FIS-lo) | Experimental | Not described Receives: Drug: Low-dose/sustained-duration Fisetin |
| Placebo | Placebo comparator | Not described Receives: Other: Oral placebo capsule |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: Change between baseline and 3-month follow-up
Secondary outcomes (5)
Pain Visual Analogue Scale (VAS)
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.
Measured: Change between baseline and 3-month follow-up
Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC)
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.
Measured: Change between baseline and 3-month follow-up
Five times sit-to-stand test
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.
Measured: Change between baseline and 3-month follow-up
Biomarker of cellular senescence (MMP-3)
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.
Measured: Change between baseline and 3-month follow-up
Biomarker of cartilage breakdown (CTXII)
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.
Measured: Change between baseline and 3-month follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Feb 2021
- Study startJun 2023 (estimated)
- Primary completion31 May 2024 (estimated)
- Study completion31 May 2024 (estimated)
Why it stopped: Funding was not awarded
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Osteoarthritis, KneeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Austin V Stone
- Sponsor type
- University, hospital or other
- Collaborators
- Brigham and Women's Hospital
- Responsible party
- Sponsor-investigator, Austin V Stone, University of Kentucky
- Investigators
- Austin Stone, MD, PhD, Principal investigator, University of Kentucky
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04770064
- Sponsor's protocol ID
- 65448
- Acronym
- ROPE
- Status last verified
- Jul 2022
- First submitted
- 16 Feb 2021
- Last updated
- 29 Jul 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Individual participant data (IDP) will not be made available to other researchers.
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeting Senescence to Reduce Osteoarthritis Pain and cartilagE Breakdown (ROPE)
- ClinicalTrials.gov ID
- NCT04770064
- Acronym / sponsor ID
- ROPE / 65448
- Conditions
- Osteoarthritis, Knee
- Keywords
- Knee, Osteoarthritis, Pain, Inflammation
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Funding was not awarded
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Austin V StoneUniversity, hospital or other
- Collaborators
- Brigham and Women's Hospital
- Study start
- Jun 2023 (estimated)
- Primary completion
- 31 May 2024 (estimated)
- Study completion
- 31 May 2024 (estimated)
- First posted
- 25 Feb 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 35 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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;
Key exclusion criteria (26 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| High-dose/short-duration FisetinFisetin 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. | Drug | High-dose/short-duration Fisetin (FIS-hi) |
| Low-dose/sustained-duration FisetinFisetin 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. | Drug | Low-dose/sustained duration Fisetin (FIS-lo) |
| Oral placebo capsuleParticipants will be asked to take one, 100 mg oral placebo capsule (corn starch) daily for 90 days. | Other | Placebo |
Primary outcome
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 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.
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.
5 secondary outcomes
Pain Visual Analogue Scale (VAS)
Time frame: Change between baseline and 3-month follow-up
Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC)
Time frame: Change between baseline and 3-month follow-up
Five times sit-to-stand test
Time frame: Change between baseline and 3-month follow-up
Biomarker of cellular senescence (MMP-3)
Time frame: Change between baseline and 3-month follow-up
Biomarker of cartilage breakdown (CTXII)
Time frame: Change between baseline and 3-month follow-up
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2022.
- Individual participant dataSharing planned: No. Individual participant data (IDP) will not be made available to other researchers.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Austin Stone, MD, PhD principal investigator
University of Kentucky
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing High-dose/short-duration Fisetin and Low-dose/sustained-duration Fisetin in people with Osteoarthritis, Knee, run by Austin V Stone at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 29 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in markers of liver toxicity (time frame: Change between baseline and 3-month follow-up). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jul 2022.