GetHealthy-OA: A Program to Improve Pain and Function for Patients With Knee Osteoarthritis, Obesity, and Depression

Inclusion Criteria:

• Mild to moderate knee osteoarthritis (Kellgren/Lawrence Grade II or III)
• Obesity (Body Mass Index > 30 kg/m2)
• History of concurrent psychotropics for < 2 weeks prior to initiation of treatment oron stable doses for > 6 weeks
• Access to an internet-enabled computer/smart phone
• Willingness to comply with the study protocol and assessments
• Cleared by a medical doctor to participate

Exclusion Criteria:

• Rheumatoid arthritis
• History of cancer within 5 years of screening; unable to walk/wheelchair-bound
• Prior surgical fixation of a femur or tibia fracture
• Taking high doses of opioid pain medication (>50 milligrams of morphine equivalent perday)
• Diagnosis of a medical illness expected to worsen in the next 6 months (e.g.,malignancy)
• Active suicidal ideation or past-year psychiatric hospitalization; non-Englishspeaking
• Lifetime history of schizophrenia, bipolar disorder, or other psychotic disorder
• Current substance abuse or dependence (or a history within the past 6 months)
• Practice of yoga/meditation, or other mind body techniques once per week > 45 minwithin the last 3 months
• Engagement in regular moderate or vigorous physical exercise for >30 min daily
• Reduced or altered capacity due to administration of any mind-altering substances suchas tranquilizers, conscious sedation or anesthesia, or brain injury
• Females who are nursing, pregnant or planning to become pregnant during the durationof study drug dosing
• Females or males who do not wish to abstain from sex or use contraceptive protectionduring study drug dosing and for 2 weeks after the last dose o Those not willing to use 2 of the following effective forms of contraception:sterilization surgery, intrauterine device (IUD), implantable rod, contraceptiveshot/injection, oral contraceptives, patch, vaginal ring, diaphragm with spermicide,sponge with spermicide, cervical cap with spermicide, and/or a male or female condom
• 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 statedtime window.
• Surgery on the Study Knee in the past 6 months
• Partial or complete joint replacement in the study knee. Partial or completejoint replacement in the contralateral knee is acceptable as long as the surgerywas performed at least 6 months prior to enrollment and the operative knee isasymptomatic
• Patients who have undergone arthroscopic surgery (including microfracture andmeniscectomy) on the Study Knee in the last 2 years prior to the Screening visitor are anticipated to have arthroscopic surgery on either knee at any time duringthe study period
• Currently taking Losartan
• Currently taking Warfarin or related anticoagulants
• Senolytic agents taken within the past 6 months and are not willing todiscontinue these medications through the duration of the study, including:Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax
• Drugs that induce significant cellular stress and are not willing to discontinuethese medications through the duration of the study, including alkylating agents,anthracyclines, platins, other chemotherapy drugs
• Medications that are sensitive substrates or substrates with a narrow therapeuticrange for cytochrome P450 family 1 subfamily A member 2 (CYP1A2), cytochrome P450family 2 subfamily C member 8 (CYP2C8), cytochrome P450 family 2 subfamily Cmember 9 (CYP2C9), cytochrome P450 family 2 subfamily C member 19 (CYP2C19),cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3subfamily A member 4 (CYP3A4), Organic Anion Transporting Polypeptide 1B1 (OATP1B1) or strong inhibitors or inducers of Cytochrome P450 3A4 (CYP3A4; e.g.cyclosporine, tacrolimus or sirolimus)
• Subjects taking the following other drugs if they cannot be held (per the MedicalDirector Austin Stone, MD, PhD) for at least 2 days before and duringadministration of Fisetin: cyclosporine, tacrolimus, repaglinide, and bosentan
• Significant liver disease (i.e. greater than or equal to 2x the upper limit ofnormal bilirubin levels) or as in the opinion of the Medical Director
• Significant renal disease (estimated glomerular filtration rate (eGFR) of <60ml/min/1.73m2) or as in the opinion of the Medical Director
• History of other formally diagnosed joint diseases including osteonecrosis,acromegaly, Paget's disease, Ehlers-Danlos Syndrome, Gaucher's disease, Cushing'ssyndrome, Stickler's syndrome, joint infection, hemophilia, hemochromatosis, orneuropathic arthropathy of any cause
• Patients with type 1 or 2 diabetes (Hemoglobin A1c (HbA1c) > 6.5%) and/or takingmedications that affect insulin levels, including: Metformin (within the lastweek), Glucocorticoids (within the last month), Acarbose (within the last week)