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| Name | Class |
|---|---|
| United States Department of Defense | FED |
| Office of Naval Research (ONR) | FED |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fisetin | Experimental | 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) |
|
| Placebo | Placebo Comparator | 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fisetin | Dietary Supplement | Fisetin will be administered orally at 20 mg/kg for two consecutive days, followed by 28 days off, then 2 more consecutive days. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Duration of study, an average of 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Subjects will be included if all the following criteria are met:
Exclusion Criteria:
Subjects will be excluded if any of the following criteria are met:
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.
Subjects with any of the following drug/medication statuses:
Subjects with any of the following disease statuses:
Subjects unable to safely practically undergo an MRI (BMI > 40 kg/m2) or size exceeding limits of MRI equipment, implanted metal in study knee near joint surface, incompatible implant/device, severe claustrophobia;
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.
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| Name | Affiliation | Role |
|---|---|---|
| Thomas A Evans, MD | The Steadman Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Steadman Clinic | Vail | Colorado | 81657 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
All randomized.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | All participants randomized and dosed with study medication. | Posted | Count of Participants | Participants | Duration of study, an average of 12 months |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rotator Cuff Injury | Musculoskeletal and connective tissue disorders | CTCAE (Unspecified) | Systematic Assessment | Rotator cuff repair secondary to massive rotator cuff tear. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Arthralgia | Musculoskeletal and connective tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Suzanne Liv Page | Vice President of Operations | 970-401-8770 | spage@sprivail.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Jun 11, 2021 | May 7, 2024 | Prot_SAP_ICF_002.pdf |
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| ID | Term |
|---|---|
| D020370 | Osteoarthritis, Knee |
| D007249 | Inflammation |
| D010003 | Osteoarthritis |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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| ID | Term |
|---|---|
| C017875 | fisetin |
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|
| Placebo oral capsule | Drug | Placebo will be administered orally for two consecutive days, followed by 28 days off, then 2 more consecutive days. |
|
|
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Any time during 18-month monitoring period. |
| Protocol Violation |
|
| Physician Decision |
|
| BG001 |
| 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | 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. |
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | ug/ml | 14 days, 45 days, 6 months, 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | ng/ml | 14 days, 45 days, 6 months, 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | Meters | 6 months, and 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | seconds | 6 months, and 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | meters/second | 6 months, and 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | Newton*meter / (kilogram*meter) | 6 months, and 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | seconds | 6 months, and 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | Newton-meters (Nm) | 6 months, and 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | score on a scale | every 3 days for the first 6-weeks of drug dosing, then weekly for an additional 6 weeks. |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | score on a scale | 6 months, 12 months, and 18 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | 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. | Posted | Least Squares Mean | Standard Error | Unitless | 6 months, and 12 months (post 1st drug dose) |
|
|
|
|
| Secondary | 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. | The analysis dataset is comprised of all randomized study participants. | Posted | Count of Participants | Participants | Any time during 18-month monitoring period. |
|
|
|
|
| 0 |
| 34 |
| 2 |
| 34 |
| 28 |
| 34 |
| EG001 | 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. | 0 | 40 | 2 | 40 | 33 | 40 |
|
| Back pain | Musculoskeletal and connective tissue disorders | CTCAE (Unspecified) | Systematic Assessment | Low back pain treated with lumbar microdiscectomy. |
|
| Bladder Perforation | Renal and urinary disorders | CTCAE (Unspecified) | Systematic Assessment | Iatrogenic bladder injury during hip replacement surgery. |
|
| Tracheal Stenosis | Respiratory, thoracic and mediastinal disorders | CTCAE (Unspecified) | Systematic Assessment | Surgery for subglottic stenosis. |
|
| Pain in Extremity | Musculoskeletal and connective tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Dry Mouth | Gastrointestinal disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Lab Findings | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Covid 19 | General disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Headache | Nervous system disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Rash Maculo-Papular | Skin and subcutaneous tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
| Neoplasms | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | CTCAE (Unspecified) | Systematic Assessment |
|
| Muscle Cramp | Musculoskeletal and connective tissue disorders | CTCAE (Unspecified) | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D010335 |
| Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| C-reactive protein (CRP): Day 45 |
|
|
| C-reactive protein (CRP): Month 6 |
|
|
| C-reactive protein (CRP): Month 12 |
|
|
| Superiority |
| DAY 45 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.9728 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -2.5 | 2-Sided | 95 | -7.8 | 2.8 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| MONTH 6 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.0829 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -20.5 | 2-Sided | 95 | -37.7 | -3.3 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Contrast of LS Means | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.9728 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.5 | 2-Sided | 95 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| COMP: Day 45 |
|
|
| COMP: Month 6 |
|
|
| COMP: Month 12 |
|
|
| Superiority |
| DAY 45 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 11.0 | 2-Sided | 95 | -36.8 | 58.8 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| MONTH 6 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.6594 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -40.3 | 2-Sided | 95 | -97.6 | 17.1 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -6.9 | 2-Sided | 95 | -45.5 | 31.7 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| Walk Distance: Month 12 |
|
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| Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.9572 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.6 | 2-Sided | 95 | -22.2 | 21.1 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| Up and go time: Month 12 |
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| Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.07 | 2-Sided | 95 | -0.33 | 0.47 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| Walk Time: Month 12 |
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| Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.16 | 2-Sided | 95 | -0.80 | 1.13 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| Adduction Moment (affected): Month 12 |
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| Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.130 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.024 | 2-Sided | 95 | -0.049 | 0.002 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| Stairs Time: Month 12 |
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| Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.9584 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.12 | 2-Sided | 95 | -0.69 | 0.92 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| Quad Torque (affected): Month 12 |
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| Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.5414 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 3.86 | 2-Sided | 95 | -3.08 | 10.79 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| NRS Pain Today: Day 6 |
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| NRS Pain Today: Day 9 |
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| NRS Pain Today: Day 12 |
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| NRS Pain Today: Day 15 |
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| NRS Pain Today: Day 18 |
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| NRS Pain Today: Day 21 |
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| NRS Pain Today: Day 24 |
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| NRS Pain Today: Day 27 |
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| NRS Pain Today: Day 30 |
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| NRS Pain Today: Day 33 |
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| NRS Pain Today: Day 36 |
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| NRS Pain Today: Day 39 |
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| NRS Pain Today: Day 42 |
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| NRS Pain Today: Week 7 |
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| NRS Pain Today: Week 8 |
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| NRS Pain Today: Week 9 |
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| NRS Pain Today: Week 10 |
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| NRS Pain Today: Week 11 |
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| NRS Pain Today: Week 12 |
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| Superiority |
| DAY 6 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.44 | 2-Sided | 95 | -0.45 | 1.34 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 9 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.42 | 2-Sided | 95 | -0.70 | 1.54 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.06 | 2-Sided | 95 | -0.91 | 0.78 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 15 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.47 | 2-Sided | 95 | -1.50 | 0.56 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 18 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.19 | 2-Sided | 95 | -1.16 | 0.77 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 21 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.19 | 2-Sided | 95 | -0.58 | 0.96 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 24 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.10 | 2-Sided | 95 | -0.76 | 0.97 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 27 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.01 | 2-Sided | 95 | -0.74 | 0.76 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 30 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.38 | 2-Sided | 95 | -1.20 | 0.44 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 33 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.10 | 2-Sided | 95 | -0.69 | 0.89 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 36 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.20 | 2-Sided | 95 | -1.02 | 0.61 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 39 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.11 | 2-Sided | 95 | -0.70 | 0.92 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| DAY 42 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.62 | 2-Sided | 95 | -1.36 | 0.13 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| WEEK 7 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.23 | 2-Sided | 95 | -1.01 | 0.55 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| WEEK 8 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.20 | 2-Sided | 95 | -0.89 | 0.49 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| WEEK 9 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | 0.02 | 2-Sided | 95 | -0.63 | 0.67 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| WEEK 10 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.17 | 2-Sided | 95 | -0.95 | 0.61 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| WEEK 11 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.42 | 2-Sided | 95 | -1.18 | 0.34 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| WEEK 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.35 | 2-Sided | 95 | -1.41 | 0.71 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| WOMAC Total: Month 12 |
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| WOMAC Total: Month 18 |
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| Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.4424 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -4.20 | 2-Sided | 95 | -9.93 | 1.53 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| MONTH 18 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | 0.9901 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -0.03 | 2-Sided | 95 | -5.55 | 5.48 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |
| Sum of Ranks Mean T2: Month 12 |
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Direction of Estimation Parameter: Placebo - Fisetin
| Superiority |
| MONTH 12 ASSESSMENT. Null hypothesis: no difference in baseline-adjusted least squares means between Fisetin and Placebo groups at each post-intervention assessment. A priori power calculation was based a standardized mean difference effect size of SMD=0.73 (Mackay, et al, 2018, Osteoarthritis and Cartilage). | Mixed Models Analysis | Mixed model for repeated measures (mmrm). Baseline measurement included as covariate. Random intercept and slope. Kenward-Roger DF. | >0.99 | A priori threshold for statistical significance = 0.05. P-values adjusted for the number of post-intervention assessments via Holm-Bonferroni method. | Contrast of LS Means | -11.3 | 2-Sided | 95 | -46.9 | 24.2 | Direction of Estimation Parameter: Placebo - Fisetin | Superiority |