Phase I/II randomized, double-blind, placebo-controlled clinical trial to test the safety and efficacy of Fisetin for treating mild to moderate osteoarthritis
This is a Phase I/II randomized, double-blind, placebo-controlled clinical trial that will be conducted at The Steadman Clinic (TSC) and Steadman Philippon Research Institute (SPRI). The purpose of this study is to evaluate the clinical efficacy of Fisetin (FIS), a dietary supplement, in symptomatic knee osteoarthritis (OA) patients. Key aspects of this proposal include the investigator's well-developed methodologies to measure and compare systemic senescence-associated secretory phenotype (SASP) including inflammatory biomarkers and senescent cells, and collect magnetic resonance images, self-reported outcomes, physical performance and other objective clinical data. Given the drug FIS has been empirically demonstrated to reduce senescent cell burden, the main objective(s) are to determine 1) the safety of FIS during dosing and 2) whether FIS reduces senescent cells, pro-inflammatory and cartilage degenerating SASP markers, and reduces OA-symptoms leading to improved joint health and function.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
75
Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
The Steadman Clinic
Vail, Colorado, United States
Number of Participants Experiencing One or More Treatment-Emergent Adverse Event
Number of Participants Experiencing one or more Treatment-Emergent Adverse Event (TEAE) within each group.
Time frame: Duration of study, an average of 12 months
Change in Levels of Pro-inflammatory Markers Associated With Senescence
Serum C-reactive protein (CRP) level measured on ELISA. The enzyme linked immunoassay (ELISA) is a laboratory technique that detects certain antigens in the blood. ELISA was used to detect the level of CRP in the blood. The liver releases CRP into blood in response to inflammation. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: 14 days, 45 days, 6 months, 12 months (post 1st drug dose)
Change in Levels of Cartilage Degenerating Markers Associated With OA
Serum cartilage oligomeric matrix protein (COMP) level measured on ELISA. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: 14 days, 45 days, 6 months, 12 months (post 1st drug dose)
Change in Physical Function of the Study Knee (6 Min Walk)
The 6 minute walk test (6MWT) assesses distance (in meters) walked over 6 minutes as a sub-maximal test of aerobic capacity, exercise tolerance and endurance. The score range for healthy adults is 400-700 m, depending on age and sex. Shorter distances indicate increased impairment. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: 6 months, and 12 months (post 1st drug dose)
Change in Physical Function of the Study Knee (Timed-up-and-go Test)
The Timed Up and Go (TUG) test measures how long it takes (in seconds) to stand up, walk a distance of 10 feet, turn, walk back, and sit down again. \< 10 seconds is considered normal. Longer times indicate poorer function. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
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Time frame: 6 months, and 12 months (post 1st drug dose)
Change in Physical Function of the Study Knee (Fast 4-meter Walk)
fast 4-meter walk test (4MW). The 4MW was assessed at the fastest safe speed for each participant. This test assesses the capacity for performance of certain activities (e.g., crossing a street before the light changes). Units are m/s, and slower speeds indicate greater impairment. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: 6 months, and 12 months (post 1st drug dose)
Change in Physical Function of the Study Knee (LEK)
Peak knee adduction moment (KAM) during stance phase of gait in the affected leg, determined using video-motion analysis and force plate data. Values are normalized by mass\*height of participant. Higher KAM has been associated with more rapid osteoarthritis progression. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: 6 months, and 12 months (post 1st drug dose)
Change in Physical Function of the Study Knee (Stair-Climbing Test)
The Stair-Climbing Test assesses the time required (in seconds) to ascend and descend a standard flight of 10 stairs. Longer times indicate poorer physical function. Stairs require greater knee extensor force than gait, so this test may be more sensitive to osteoarthritis pain and function than walking tests. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: 6 months, and 12 months (post 1st drug dose)
Change in Muscle Strength (Isokinetic Dynamometry)
This test utilizes an isokinetic dynamometer to assess the peak knee extension torque that can be produced by the affected leg at a constant rate of knee extension (60 degrees/s). The resulting measure is normalized by body mass and reported with units Newton-meters (Nm). Increased torque over time would indicate improved muscle strength and/or decreased joint pain. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: 6 months, and 12 months (post 1st drug dose)
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain
Numeric Rating Scale (NRS) reporting 'pain today'. Scale of 0-10 with 0 representing 'no pain' and 10 representing 'severe pain'. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: every 3 days for the first 6-weeks of drug dosing, then weekly for an additional 6 weeks.
Evaluation of Patient Reported Outcomes (PROs) for Knee Function
Western Ontario and McMaster Universities Arthritis Index (WOMAC) - total score. Scores range from 0 to 96 for the total WOMAC where 0 represents the best health status and 96 the worst possible status. The higher the score, the poorer the function. All post-intervention group comparisons were adjusted for the baseline value as a covariate.
Time frame: 6 months, 12 months, and 18 months (post 1st drug dose)
Change in the Quality of Articular Cartilage in the Study Knee With Quantitative Magnetic Resonance Imaging (MRI)
Mean T2 relaxation times were determined across 4 subregions: central medial femur (CMF), central lateral femur (CLF), central medial tibia (CMT), and central lateral tibia (CLT). All post-intervention group comparisons were adjusted for the baseline value as a covariate. The mean T2 changes over time for all subregions were listed in rank order from most positive (indicating worsened cartilage condition over time) to most negative (indicating improved cartilage condition over time). These unitless rankings were used in a Sum of Ranks statistical analysis to compare cartilage changes across different knee joint regions without assuming normality (as appropriate for MRI data). There are no published standards for what would be considered a clinically significant effect for sum-of-ranks cartilage T2 data, so it was assumed that a statistically significant difference would imply clinical significance as well.
Time frame: 6 months, and 12 months (post 1st drug dose)
Number of Participants Who Convert to Alterative Treatment Within Each Group.
Patients will be allowed to receive a steroid injection and still participate in the study. All participants that undergo alternative therapy (e.g. total knee arthroplasty or biologic injection) will be recorded, and proportions will be compared between groups.
Time frame: Any time during 18-month monitoring period.