Clinical trial NCT04210986: Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial
Official title: Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Osteoarthritis, Knee
Keywords: Fisetin
Inflammation
Osteoarthritis
Lead sponsor: Steadman Philippon Research Institute
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
name: Office of Naval Research (ONR)
First posted: 2019-12-26
Enrollment: 75
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Phase I/II randomized, double-blind, placebo-controlled clinical trial to test the safety and efficacy of Fisetin for treating mild to moderate osteoarthritis

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Subjects will be included if all the following criteria are met:

1. Are male or female, ages 40-80;
2. Are willing to comply with all study related procedures and assessments;
3. Are ambulatory as defined by ability to complete functional performance testing;
4. Radiographic evidence of Kellgren-Lawrence grade II-IV osteoarthritis in one or both knees;
5. Scores 4-10 on the Numerical Rating Scale (NRS) for pain;
6. Stable dose of screening/baseline medications for at least 2 months prior to the anticipated date of study drug dosing.

Exclusion Criteria:

Subjects will be excluded if any of the following criteria are met:

1. Females who are nursing, pregnant or planning to become pregnant during the duration of study drug dosing;
2. 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;
3. Subjects who do not have the capacity to consent themselves;
4. Subjects who are unable to tolerate oral medication;
5. Subjects having previously undergone any of the following treatments in the stated time window.

   * Surgery on the Study Knee in the past 6 months;
   * Partial or complete joint replacement in the study knee. Partial or complete joint replacement in the contralateral knee is acceptable as long as the surgery was performed at least 6 months prior to enrollment and the operative knee is asymptomatic;
   * Patients who have undergone arthroscopic surgery (including microfracture and meniscectomy) on the Study Knee in the last 2 years prior to the Screening visit or are anticipated to have arthroscopic surgery on either knee at any time during the study period;
   * Steroid injection, including extended-release corticosteroid (e.g., Zilretta®) within the last 5 months;
   * Biologic (platelet-rich plasma, bone marrow, adipose tissue/cells) or hyaluronic acid injection into the Study Knee in the past 6 months;
6. Subjects with any of the following drug/medication statuses:

   * Currently taking Losartan;
   * Currently taking Warfarin or related anticoagulants;
   * Opioid analgesics taken in the past 8 weeks and are not willing to discontinue these medications through the duration of the study;
   * Senolytic agents taken within the past 6 months and are not willing to discontinue these medications through the duration of the study, including: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax;
   * Drugs that induce significant cellular stress and are not willing to discontinue these medications through the duration of the study, including alkylating agents, anthracyclines, platins, other chemotherapy drugs;
   * Subjects taking the following other drugs if they cannot be held (per the Principal Investigator) for at least 2 days before and during administration of Fisetin: cyclosporine, tacrolimus, repaglinide, and bosentan.
7. Subjects with any of the following disease statuses:

   * Significant liver disease (i.e. greater than or equal to 2x the upper limit of normal bilirubin levels) or as in the opinion of the Principal Investigator;
   * Significant renal disease (eGFR of \<60 ml/min/1.73m2) or as in the opinion of the Principal Investigator;
   * History of other formally diagnosed joint diseases including osteonecrosis, acromegaly, Paget's disease, Ehlers-Danlos Syndrome, Gaucher's disease, Cushing's syndrome, Stickler's syndrome, joint infection, hemophilia, hemochromatosis, or neuropathic arthropathy of any cause;
   * Any active systemic autoimmune disease with musculoskeletal involvement or any history of system inflammatory arthritis;
   * Patients with type 1 or 2 diabetes (HbA1c\>6.5%) and/or taking medications that affect insulin levels, including: Metformin (within the last week), Glucocorticoids (within the last month), Acarbose (within the last week);
8. 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;
9. 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.

Primary outcomes:
measure: Number of Participants Experiencing One or More Treatment-Emergent Adverse Event
timeFrame: Duration of study, an average of 12 months
Secondary outcomes:
measure: Change in Levels of Pro-inflammatory Markers Associated With Senescence
timeFrame: 14 days, 45 days, 6 months, 12 months (post 1st drug dose)
measure: Change in Levels of Cartilage Degenerating Markers Associated With OA
timeFrame: 14 days, 45 days, 6 months, 12 months (post 1st drug dose)
measure: Change in Physical Function of the Study Knee (6 Min Walk)
timeFrame: 6 months, and 12 months (post 1st drug dose)
measure: Change in Physical Function of the Study Knee (Timed-up-and-go Test)
timeFrame: 6 months, and 12 months (post 1st drug dose)
measure: Change in Physical Function of the Study Knee (Fast 4-meter Walk)
timeFrame: 6 months, and 12 months (post 1st drug dose)
measure: Change in Physical Function of the Study Knee (LEK)
timeFrame: 6 months, and 12 months (post 1st drug dose)
measure: Change in Physical Function of the Study Knee (Stair-Climbing Test)
timeFrame: 6 months, and 12 months (post 1st drug dose)
measure: Change in Muscle Strength (Isokinetic Dynamometry)
timeFrame: 6 months, and 12 months (post 1st drug dose)
measure: Evaluation of Patient Reported Outcomes (PROs) for Knee Pain
timeFrame: every 3 days for the first 6-weeks of drug dosing, then weekly for an additional 6 weeks.
measure: Evaluation of Patient Reported Outcomes (PROs) for Knee Function
timeFrame: 6 months, 12 months, and 18 months (post 1st drug dose)
measure: Change in the Quality of Articular Cartilage in the Study Knee With Quantitative Magnetic Resonance Imaging (MRI)
timeFrame: 6 months, and 12 months (post 1st drug dose)
measure: Number of Participants Who Convert to Alterative Treatment Within Each Group.
timeFrame: Any time during 18-month monitoring period.
Other outcomes:
Locations:
city: Vail
country: United States
facility: The Steadman Clinic
state: Colorado
Study officials:
affiliation: The Steadman Clinic
name: Thomas A Evans, MD
role: PRINCIPAL_INVESTIGATOR
References: