The Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis
Overview
- Phase
- Phase 1
- Intervention
- Fisetin
- Conditions
- Osteoarthritis, Knee
- Sponsor
- Steadman Philippon Research Institute
- Enrollment
- 100
- Locations
- 1
- Primary Endpoint
- Incidence of Treatment-Emergent Adverse Events
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a prospective, randomized, double-blind, active control clinical trial to evaluate the safety and efficacy of a senolytic agent (Fisetin) and an anti-fibrotic agent (Losartan), used independently and in combination, to improve beneficial effect demonstrated by the active control which is to be injection of autologous bone marrow aspirate concentrate (BMAC) into an osteoarthritic knee.
Detailed Description
This is a prospective, randomized, double-blind, active control clinical trial to evaluate the safety and efficacy of a senolytic agent (Fisetin) and an anti-fibrotic agent (Losartan), used independently and in combination, to improve beneficial effect demonstrated by the active control which is to be injection of autologous bone marrow aspirate concentrate (BMAC) into an osteoarthritic knee. 100 subjects with symptomatic unilateral or bilateral knee osteoarthritis (Kellgren-Lawrence grade II-IV) will be randomized into one of four arms (1:1:1:1). All subjects will receive an injection of BMAC. Group 1-n=25: Control (BMA concentrate + Fisetin Placebo + Losartan Placebo) Group 2-n=25: BMA concentrate + Fisetin Placebo + Active Losartan Group 3-n=25: BMA concentrate + Active Fisetin + Losartan Placebo Group 4-n=25: BMA concentrate + Active Fisetin + Active Losartan
Investigators
Eligibility Criteria
Inclusion Criteria
- •Capacity to personally give informed consent (consent via legally authorized representative will not be accepted) and who are willing to comply with all study-related procedures and assessments;
- •Between 40 and 85 years of age;
- •Ambulatory persons with osteoarthritis (OA) of at least one knee (Kellgren-Lawrence grade II-IV);
- •Baseline pain of 3-10 points on the target knee and a pain differential of at least -2 points on the contralateral knee as exhibited by the worst pain score (on the 11-point Numeric Rating Scale) for the previous week.
Exclusion Criteria
- •Previous or Planned Knee Surgeries, Procedures and/or Treatments:
- •Planned surgery on either the contralateral or target knee at any time during the Study period including dosing and follow-up;
- •Within 6 months of signing informed consent has received diagnostic arthroscopy of the target knee or arthroscopic surgery (including microfracture and meniscectomy) on the target knee;
- •Within 12 weeks of signing informed consent has received intra-articular treatment of the target knee with steroids or hyaluronic acid derivatives;
- •History of previous total or partial arthroplasty in the target knee. Partial or total arthroplasty 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;
- •Current and/or Previous Medical Conditions, Surgeries and/or Procedures:
- •Within 2 years of signing informed consent history of active blood disorders (i.e., DVTs, chronic blood clotting, hemophilia, leukemia, myeloma, etc.); or active malignancy of any type or history of a malignancy (with the exception of subjects with a history of treated basal or squamous cell carcinoma);
- •Current diagnosis of fibromyalgia based on ACR criteria;
- •History of diabetes mellitus according to the American Diabetes Association criteria, or subjects previously diagnosed by a qualified physician as having diabetes (American Diabetes Association Standards of Medical Care in Diabetes 2016);
- •Any active known or suspected systemic autoimmune disease (except for vitiligo, residual auto-immune hypothyroidism requiring hormone replacement only, psoriasis not requiring systemic treatment for two years, conditions not expected to recur in the absence of an external trigger) or any history of a systemic inflammatory arthritis such as psoriatic, rheumatoid, ankylosing spondylitis or reactive arthritis;
Arms & Interventions
Active Fisetin and Active Losartan
Losartan 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).
Intervention: Fisetin
Active Fisetin and Active Losartan
Losartan 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).
Intervention: Losartan
Active Fisetin and Losartan Placebo
Losartan Placebo 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).
Intervention: Fisetin
Active Fisetin and Losartan Placebo
Losartan Placebo 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).
Intervention: Placebo - Losartan
Fisetin Placebo and Active Losartan
Losartan 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin Placebo 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).
Intervention: Losartan
Fisetin Placebo and Active Losartan
Losartan 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin Placebo 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).
Intervention: Placebo Fisetin
Control
Losartan placebo 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin Placebo 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).
Intervention: Placebo - Losartan
Control
Losartan placebo 12.5 mg, PO, BID beginning the first day after BMA Concentrate injection and continuing for 30 days. Fisetin Placebo 20mg/kg taken a total of 4 days prior to BMA Concentrate injection (-32 and -31 and -3 and -2) then again after BMA Concentrate injection a for a total of 6 days (32 \& 33, 61 \& 62 and 90 \& 91).
Intervention: Placebo Fisetin
Outcomes
Primary Outcomes
Incidence of Treatment-Emergent Adverse Events
Time Frame: Adverse events will be collected from the date of BMAC injection to 12 months after injection
Occurrence of adverse events
Secondary Outcomes
- Morphological and Quantitative Magnetic Resonance Imaging (MRI)(32 days - 3 months prior to injection, 6 months post injection, 12 months post injection))
- Evaluation of patient reported outcome (PRO) for quality of life(within 3 months of injection, 32 days post baseline, 14 days post injection, 30 days post injection, 3 months post injection, 6 months post injection, 12 months post injection, 18 months post injection)
- Evaluation of patient reported outcome (PRO) for knee functions (WOMAC)(within 3 months of injection, 32 days post baseline, 14 days post injection, 30 days post injection, 3 months post injection, 6 months post injection, 12 months post injection, 18 months post injection)
- Evaluation of patient reported outcome (PRO) for knee functions (Tegner)(within 3 months of injection, 32 days post baseline, 14 days post injection, 30 days post injection, 3 months post injection, 6 months post injection, 12 months post injection, 18 months post injection)
- Evaluation of patient reported outcome (PRO) for knee functions (IKDC)(within 3 months of injection, 32 days post baseline, 14 days post injection, 30 days post injection, 3 months post injection, 6 months post injection, 12 months post injection, 18 months post injection)
- Patient-Reported Outcome Questionnaires(Screening, weekly post 1st study drug dose (pre-injection), weekly post injection (for 4 months))
- Change in muscle strength of the study knee(32 days - 3 months prior to injection, 6 months post injection, 12 months post injection)
- Change in physical function of the Study Knee (LEK)(32 days - 3 months prior to injection, 6 months post injection, 12 months post injection)
- Characterization of Bone Marrow Derived Aspirate Concentrate cell content prior to injection(32 days post baseline)
- Change in physical function of the Study Knee (Stair Test)(32 days - 3 months prior to injection, 6 months post injection, 12 months post injection])
- Change in physical function of the Study Knee (6-minute walk test)(32 days - 3 months prior to injection, 6 months post injection, 12 months post injection])
- Change in associate biomarkers as compared to placebo in peripheral blood plasma/serum(screening, 14 days post-injection, 30 days post injection, 3 months post injection, 6 months post injection, 12 months post injection)
- Change in CTX-II as compared to placebo in urine(32 days post baseline, 6 months post injection, 12 months post injection)
- Change in levels of senescent PBMCS (total and specific PBMC subsets such as T-Cells)(screening, 14 days post-injection, 30 days post injection, 3 months post injection, 6 months post injection, 12 months post injection)
- Change in synovial fluid content(32 days post baseline, 6 months post injection, 12 months post injection)
- Change in physical function of the Study Knee (fast 40-meter walk)(32 days - 3 months prior to injection, 6 months post injection, 12 months post injection)
- Change in physical function of the Study Knee (TUG)(32 days - 3 months prior to injection, 6 months post injection, 12 months post injection)
- Characterization of Bone Marrow Derived plasma biomarkers prior to injection(32 days post baseline)
- Change in time to conversion to alternative treatment(Subjects may receive alternative treatment at any point during the 18-month study, continued participation will be determined on an individual basis (The time to resort to alternative therapy from baseline will be recorded))