Trial Outcomes & Findings for Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial (NCT NCT04210986)

NCT ID: NCT04210986

Last Updated: 2024-09-19

Results Overview

Number of Participants Experiencing one or more Treatment-Emergent Adverse Event (TEAE) within each group.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

75 participants

Primary outcome timeframe

Duration of study, an average of 12 months

Results posted on

2024-09-19

Participant Flow

Participant milestones

Participant milestones
Measure	Fisetin Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Overall Study STARTED	34	40
Overall Study COMPLETED	25	35
Overall Study NOT COMPLETED	9	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Fisetin Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Overall Study Lost to Follow-up	5	2
Overall Study Withdrawal by Subject	3	1
Overall Study Protocol Violation	1	1
Overall Study Physician Decision	0	1

Baseline Characteristics

Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Total n=74 Participants Total of all reporting groups
Age, Continuous	62 years n=5 Participants	64 years n=7 Participants	63 years n=5 Participants
Sex: Female, Male Female	20 Participants n=5 Participants	24 Participants n=7 Participants	44 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	33 Participants n=5 Participants	39 Participants n=7 Participants	72 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	34 Participants n=5 Participants	38 Participants n=7 Participants	72 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	34 participants n=5 Participants	40 participants n=7 Participants	74 participants n=5 Participants

PRIMARY outcome

Timeframe: Duration of study, an average of 12 months

Population: All participants randomized and dosed with study medication.

Number of Participants Experiencing one or more Treatment-Emergent Adverse Event (TEAE) within each group.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Number of Participants Experiencing One or More Treatment-Emergent Adverse Event	28 Participants	33 Participants

SECONDARY outcome

Timeframe: 14 days, 45 days, 6 months, 12 months (post 1st drug dose)

Population: The analysis dataset is comprised of all randomized study participants with an evaluable endpoint data captured at each assessment time point. Unavailability of endpoint data at post-intervention time points may be due to withdrawal, discontinuation, missed study visit, or otherwise unsuccessful data acquisition or processing.

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in Levels of Pro-inflammatory Markers Associated With Senescence C-reactive protein (CRP): Day 14	14.0 ug/ml Standard Error 2.5	10.5 ug/ml Standard Error 2.5
Change in Levels of Pro-inflammatory Markers Associated With Senescence C-reactive protein (CRP): Day 45	8.9 ug/ml Standard Error 1.9	6.4 ug/ml Standard Error 1.8
Change in Levels of Pro-inflammatory Markers Associated With Senescence C-reactive protein (CRP): Month 6	32.5 ug/ml Standard Error 6.4	12.0 ug/ml Standard Error 5.7
Change in Levels of Pro-inflammatory Markers Associated With Senescence C-reactive protein (CRP): Month 12	9.2 ug/ml Standard Error 1.8	8.8 ug/ml Standard Error 1.6

SECONDARY outcome

Timeframe: 14 days, 45 days, 6 months, 12 months (post 1st drug dose)

Serum cartilage oligomeric matrix protein (COMP) level measured on ELISA. All post-intervention group comparisons were adjusted for the baseline value as a covariate.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in Levels of Cartilage Degenerating Markers Associated With OA COMP: Day 14	288.3 ng/ml Standard Error 19.0	290.1 ng/ml Standard Error 17.5
Change in Levels of Cartilage Degenerating Markers Associated With OA COMP: Day 45	274.2 ng/ml Standard Error 18.1	285.2 ng/ml Standard Error 15.6
Change in Levels of Cartilage Degenerating Markers Associated With OA COMP: Month 6	282.0 ng/ml Standard Error 22.0	241.7 ng/ml Standard Error 18.2
Change in Levels of Cartilage Degenerating Markers Associated With OA COMP: Month 12	274.9 ng/ml Standard Error 14.1	268.0 ng/ml Standard Error 12.7

SECONDARY outcome

Timeframe: 6 months, and 12 months (post 1st drug dose)

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in Physical Function of the Study Knee (6 Min Walk) Walk Distance: Month 6	541.8 Meters Standard Error 8.7	552.2 Meters Standard Error 7.8
Change in Physical Function of the Study Knee (6 Min Walk) Walk Distance: Month 12	544.2 Meters Standard Error 8.0	543.6 Meters Standard Error 7.2

SECONDARY outcome

Timeframe: 6 months, and 12 months (post 1st drug dose)

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in Physical Function of the Study Knee (Timed-up-and-go Test) Up and go time: Month 6	6.08 seconds Standard Error 0.18	6.09 seconds Standard Error 0.16
Change in Physical Function of the Study Knee (Timed-up-and-go Test) Up and go time: Month 12	5.93 seconds Standard Error 0.15	6.00 seconds Standard Error 0.13

SECONDARY outcome

Timeframe: 6 months, and 12 months (post 1st drug dose)

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in Physical Function of the Study Knee (Fast 4-meter Walk) Walk Time: Month 6	22.1 meters/second Standard Error 0.46	21.7 meters/second Standard Error 0.41
Change in Physical Function of the Study Knee (Fast 4-meter Walk) Walk Time: Month 12	21.7 meters/second Standard Error 0.36	21.8 meters/second Standard Error 0.32

SECONDARY outcome

Timeframe: 6 months, and 12 months (post 1st drug dose)

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in Physical Function of the Study Knee (LEK) Adduction Moment (affected): Month 6	0.204 Newtonmeter / (kilogrammeter) Standard Error 0.009	0.182 Newtonmeter / (kilogrammeter) Standard Error 0.008
Change in Physical Function of the Study Knee (LEK) Adduction Moment (affected): Month 12	0.204 Newtonmeter / (kilogrammeter) Standard Error 0.009	0.180 Newtonmeter / (kilogrammeter) Standard Error 0.009

SECONDARY outcome

Timeframe: 6 months, and 12 months (post 1st drug dose)

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in Physical Function of the Study Knee (Stair-Climbing Test) Stairs Time: Month 6	8.88 seconds Standard Error 0.23	8.66 seconds Standard Error 0.21
Change in Physical Function of the Study Knee (Stair-Climbing Test) Stairs Time: Month 12	8.66 seconds Standard Error 0.30	8.78 seconds Standard Error 0.27

SECONDARY outcome

Timeframe: 6 months, and 12 months (post 1st drug dose)

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in Muscle Strength (Isokinetic Dynamometry) Quad Torque (affected): Month 6	81.2 Newton-meters (Nm) Standard Error 2.6	83.1 Newton-meters (Nm) Standard Error 2.3
Change in Muscle Strength (Isokinetic Dynamometry) Quad Torque (affected): Month 12	81.2 Newton-meters (Nm) Standard Error 2.6	85.0 Newton-meters (Nm) Standard Error 2.3

SECONDARY outcome

Timeframe: every 3 days for the first 6-weeks of drug dosing, then weekly for an additional 6 weeks.

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 18	2.58 score on a scale Standard Error 0.36	2.39 score on a scale Standard Error 0.32
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 21	2.25 score on a scale Standard Error 0.29	2.44 score on a scale Standard Error 0.26
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 24	2.46 score on a scale Standard Error 0.32	2.57 score on a scale Standard Error 0.29
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 39	2.15 score on a scale Standard Error 0.30	2.26 score on a scale Standard Error 0.27
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 42	2.42 score on a scale Standard Error 0.28	1.81 score on a scale Standard Error 0.24
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Week 7	2.15 score on a scale Standard Error 0.29	1.92 score on a scale Standard Error 0.26
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Week 8	2.04 score on a scale Standard Error 0.25	1.84 score on a scale Standard Error 0.23
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Week 10	1.88 score on a scale Standard Error 0.29	1.71 score on a scale Standard Error 0.26
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Week 11	1.99 score on a scale Standard Error 0.28	1.57 score on a scale Standard Error 0.25
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Week 12	2.26 score on a scale Standard Error 0.39	1.91 score on a scale Standard Error 0.36
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 3	2.80 score on a scale Standard Error 0.29	2.85 score on a scale Standard Error 0.27
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 6	2.43 score on a scale Standard Error 0.33	2.87 score on a scale Standard Error 0.30
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 9	2.35 score on a scale Standard Error 0.41	2.77 score on a scale Standard Error 0.37
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 12	2.47 score on a scale Standard Error 0.31	2.40 score on a scale Standard Error 0.28
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 15	2.65 score on a scale Standard Error 0.37	2.18 score on a scale Standard Error 0.35
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 27	2.35 score on a scale Standard Error 0.28	2.36 score on a scale Standard Error 0.25
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 30	2.58 score on a scale Standard Error 0.30	2.21 score on a scale Standard Error 0.27
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 33	2.09 score on a scale Standard Error 0.29	2.19 score on a scale Standard Error 0.27
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Day 36	2.57 score on a scale Standard Error 0.30	2.37 score on a scale Standard Error 0.27
Evaluation of Patient Reported Outcomes (PROs) for Knee Pain NRS Pain Today: Week 9	1.84 score on a scale Standard Error 0.24	1.86 score on a scale Standard Error 0.22

SECONDARY outcome

Timeframe: 6 months, 12 months, and 18 months (post 1st drug dose)

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Evaluation of Patient Reported Outcomes (PROs) for Knee Function WOMAC Total: Month 6	15.2 score on a scale Standard Error 1.8	17.1 score on a scale Standard Error 1.7
Evaluation of Patient Reported Outcomes (PROs) for Knee Function WOMAC Total: Month 12	19.6 score on a scale Standard Error 2.1	15.4 score on a scale Standard Error 1.9
Evaluation of Patient Reported Outcomes (PROs) for Knee Function WOMAC Total: Month 18	17.4 score on a scale Standard Error 2.0	17.4 score on a scale Standard Error 1.8

SECONDARY outcome

Timeframe: 6 months, and 12 months (post 1st drug dose)

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Change in the Quality of Articular Cartilage in the Study Knee With Quantitative Magnetic Resonance Imaging (MRI) Sum of Ranks Mean T2: Month 6	149.6 Unitless Standard Error 11.6	150.3 Unitless Standard Error 10.7
Change in the Quality of Articular Cartilage in the Study Knee With Quantitative Magnetic Resonance Imaging (MRI) Sum of Ranks Mean T2: Month 12	156.1 Unitless Standard Error 13.0	144.8 Unitless Standard Error 12.0

SECONDARY outcome

Timeframe: Any time during 18-month monitoring period.

Population: The analysis dataset is comprised of all randomized study participants.

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.

Outcome measures

Outcome measures
Measure	Fisetin n=34 Participants Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 Participants Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Number of Participants Who Convert to Alterative Treatment Within Each Group.	1 Participants	3 Participants

Adverse Events

Fisetin

Serious events: 2 serious events

Other events: 28 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Fisetin n=34 participants at risk Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 participants at risk Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Musculoskeletal and connective tissue disorders Rotator Cuff Injury	2.9% 1/34 • Number of events 1 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	0.00% 0/40 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/34 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	2.5% 1/40 • Number of events 1 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Renal and urinary disorders Bladder Perforation	2.9% 1/34 • Number of events 1 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	0.00% 0/40 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Respiratory, thoracic and mediastinal disorders Tracheal Stenosis	0.00% 0/34 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	2.5% 1/40 • Number of events 1 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.

Other adverse events

Other adverse events
Measure	Fisetin n=34 participants at risk Fisetin 100 mg capsules (\~20 mg/ kg/ day) will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Fisetin: Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days.	Placebo n=40 participants at risk Placebo capsules will be administered orally for two consecutive days (days 1 and 2) followed by 28 days off. A second course will be given for two consecutive days (days 31 and 32) Placebo oral capsule: Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days.
Musculoskeletal and connective tissue disorders Arthralgia	38.2% 13/34 • Number of events 17 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	42.5% 17/40 • Number of events 23 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Musculoskeletal and connective tissue disorders Pain in Extremity	14.7% 5/34 • Number of events 5 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	10.0% 4/40 • Number of events 5 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Musculoskeletal and connective tissue disorders Back Pain	8.8% 3/34 • Number of events 3 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	7.5% 3/40 • Number of events 5 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Gastrointestinal disorders Nausea	11.8% 4/34 • Number of events 4 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	12.5% 5/40 • Number of events 5 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Gastrointestinal disorders Dry Mouth	5.9% 2/34 • Number of events 3 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	2.5% 1/40 • Number of events 1 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Gastrointestinal disorders Flatulence	5.9% 2/34 • Number of events 2 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	2.5% 1/40 • Number of events 1 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Gastrointestinal disorders Constipation	0.00% 0/34 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	5.0% 2/40 • Number of events 2 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
General disorders Lab Findings	11.8% 4/34 • Number of events 8 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	7.5% 3/40 • Number of events 5 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
General disorders Fatigue	8.8% 3/34 • Number of events 3 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	7.5% 3/40 • Number of events 3 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
General disorders Covid 19	2.9% 1/34 • Number of events 1 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	5.0% 2/40 • Number of events 2 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Nervous system disorders Headache	8.8% 3/34 • Number of events 3 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	5.0% 2/40 • Number of events 3 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Skin and subcutaneous tissue disorders Rash Maculo-Papular	5.9% 2/34 • Number of events 3 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	5.0% 2/40 • Number of events 2 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms	2.9% 1/34 • Number of events 1 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	10.0% 4/40 • Number of events 5 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.
Musculoskeletal and connective tissue disorders Muscle Cramp	5.9% 2/34 • Number of events 2 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.	0.00% 0/40 • 12 months following initial administration of study medication. AE assessment occurred systematically at in-person visits at 14 days, 45 days, 6 months, and 12 months following first dose. Additionally, dosing reminder phone calls occurred at the time of subsequent dosing, at which time AEs were captured.

Additional Information

Suzanne Liv Page

Vice President of Operations

Phone: 970-401-8770

Email: [email protected]

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Principal investigator is a sponsor employee
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