- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04815902
Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis
The Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Suzanne L Page, JD
- Phone Number: 970-401-8770
- Email: spage@sprivail.org
Study Contact Backup
- Name: Luz Thede, MD
- Phone Number: 970-409-7566
- Email: lthede@sprivail.org
Study Locations
-
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Colorado
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Vail, Colorado, United States, 81657
- The Steadman Clinic
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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;
- Within 6 months of signing informed consent has undergone regenerative knee joint procedures including, but not limited to, platelet-rich plasma injections, mesenchymal stem cell transplantation, autologous chondrocyte transplantation, or mosaicplasty;
- Current or prior history of other joint diseases including but not limited to joint dysplasia, crystal-induced arthropathy (such as gout, or calcium pyrophosphate deposition disease evidenced by clinical and/or radiographic means), aseptic osteonecrosis, acromegaly, Paget's disease, Ehlers-Danlos Syndrome, Gaucher's disease, Stickler syndrome, joint infection, hemochromatosis, or neuropathic arthropathy of any cause;
- Any medical condition, including findings in laboratory or medical history or in the baseline assessments, that (in the opinion of the Principal Investigator or his designee), constitutes a risk or contraindication for participation in the Study or that could interfere with the Study conduct, endpoint evaluation or prevent the subject from fully participating in all aspects of the Study;
- Females who nursing a child, are pregnant or planning to become pregnant during study drug dosing;
- Males who do not wish to abstain from sex with women of childbearing potential without use of contraceptive protection by either party during study drug dosing;
Unable to safely undergo an MRI based on MRI safety screening (for example, due to incompatible device/implant, severe claustrophobia, BMI greater than 40 kg/m2, or size exceeding the limits of the of the MRI equipment (coil and gantry);
Current and/or Previous Medications and Supplements:
- Taking medications that affect insulin activity, including Metformin or Acarbose within 1 week of signing informed consent;
- Currently taking Losartan or Fisetin, allergy to any active or inactive ingredient of Losartan or Fisetin, and/or currently taking medication with known Losartan or Fisetin interaction;
- Within 3 months of signing informed consent have taken senolytic agents including: Fisetin, Quercetin, Luteolin, Dasatinib, Piperlongumine, or Navitoclax;
Subjects with any of the following drug/medication statuses:
- Currently taking Losartan;
- Currently taking Warfarin or related anticoagulants;
- Currently taking Lithium;
- 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 3 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.
- Taking a glucocorticoid within 1 month of signing informed consent;
- Within 8 weeks of signing informed consent has used opioid analgesics, and are not willing to discontinue these medications through the duration of the study;
- Within the 3 months of signing informed consent has received anticonvulsant therapy, pharmacological doses of thyroid hormone (causing decline of thyroid stimulating hormone below normal), calcium supplementation of > 1200 mg/d;
- Within the 12 months prior to signing informed consent received any medications that affect bone turnover, including: adrenocorticosteroids (> 3 months at any time or > 10 days, estrogen (E) therapy or treatment with a selective E receptor modulator, or teriparatide;
- Inability to tolerate oral medication;
- Inadequate amount of BMA collected to serve the needs of the patient, ProofPoint Biologics and/or of the SPRI laboratory.
Behavioral Modification - Participants will be educated about the risk of excessive caffeine usage. Participants will be encouraged to reduce use by 50% prior to and during the Fisetin dosing days. Due to drug-drug interaction, subjects may not clear the caffeine from their system properly/as usual.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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).
|
Oral Fisetin 20 mg/kg taken for 10 days total.
Other Names:
12.5 mg oral Losartan taken for 30 days total.
Other Names:
|
Active Comparator: 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).
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Oral Fisetin 20 mg/kg taken for 10 days total.
Other Names:
Losartan appearance-matched microcrystalline cellulose placebo.
12.5 taken for 30 days total.
Other Names:
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Active Comparator: 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).
|
12.5 mg oral Losartan taken for 30 days total.
Other Names:
Fisetin appearance-matched microcrystalline cellulose placebo.
20 mg/kg taken for 10 days total.
Other Names:
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Placebo Comparator: 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).
|
Losartan appearance-matched microcrystalline cellulose placebo.
12.5 taken for 30 days total.
Other Names:
Fisetin appearance-matched microcrystalline cellulose placebo.
20 mg/kg taken for 10 days total.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of Treatment-Emergent Adverse Events
Time Frame: Adverse events will be collected from the date of BMAC injection to 12 months after injection
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Occurrence of adverse events
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Adverse events will be collected from the date of BMAC injection to 12 months after injection
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Morphological and Quantitative Magnetic Resonance Imaging (MRI)
Time Frame: 32 days - 3 months prior to injection, 6 months post injection, 12 months post injection)
|
Cartilage quality assessed by blinded radiologist using morphological MRI.
Quantitative MRI using T2 mapping images with texture analysis used to assess water content and collagen organization within the cartilage and surrounding tissue
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32 days - 3 months prior to injection, 6 months post injection, 12 months post injection)
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Evaluation of patient reported outcome (PRO) for quality of life
Time Frame: 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
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12-question Short-Form General Health Survey (SF-12) - Including Physical Component Summary (PCS) and Mental Component Summary (MCS).
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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
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Evaluation of patient reported outcome (PRO) for knee functions (WOMAC)
Time Frame: 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
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The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (24 questions; rated none, mild, moderate, or severe.
Higher WOMAC score represents higher disability)
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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
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Evaluation of patient reported outcome (PRO) for knee functions (Tegner)
Time Frame: 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
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Tegner Physical Activity Scale (1 question; scale of 0 to10; 0 representing a low activity level and 10 representing a high activity level)
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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
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Evaluation of patient reported outcome (PRO) for knee functions (IKDC)
Time Frame: 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
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International Knee Documentation Committee (IKDC) Form.
(scores range from 0 points or lowest level of function, to 100 points or highest level of function)
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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
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Patient-Reported Outcome Questionnaires
Time Frame: Screening, weekly post 1st study drug dose (pre-injection), weekly post injection (for 4 months)
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Numerical Rating Scale (NRS) for knee pain (6 questions with a scale of 0 to 10; 0 representing no pain and 10 representing extreme pain)
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Screening, weekly post 1st study drug dose (pre-injection), weekly post injection (for 4 months)
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Change in muscle strength of the study knee
Time Frame: 32 days - 3 months prior to injection, 6 months post injection, 12 months post injection
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Isokinetic Dynamometry
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32 days - 3 months prior to injection, 6 months post injection, 12 months post injection
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Change in physical function of the Study Knee (LEK)
Time Frame: 32 days - 3 months prior to injection, 6 months post injection, 12 months post injection
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Lower Extremity Kinematics
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32 days - 3 months prior to injection, 6 months post injection, 12 months post injection
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Change in physical function of the Study Knee (Stair Test)
Time Frame: 32 days - 3 months prior to injection, 6 months post injection, 12 months post injection]
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Stair Test
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32 days - 3 months prior to injection, 6 months post injection, 12 months post injection]
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Change in physical function of the Study Knee (fast 40-meter walk)
Time Frame: 32 days - 3 months prior to injection, 6 months post injection, 12 months post injection
|
Fast 40-meter walk
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32 days - 3 months prior to injection, 6 months post injection, 12 months post injection
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Change in physical function of the Study Knee (TUG)
Time Frame: 32 days - 3 months prior to injection, 6 months post injection, 12 months post injection
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Timed up-and-go test
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32 days - 3 months prior to injection, 6 months post injection, 12 months post injection
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Change in physical function of the Study Knee (6-minute walk test)
Time Frame: 32 days - 3 months prior to injection, 6 months post injection, 12 months post injection]
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6-minute walk test
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32 days - 3 months prior to injection, 6 months post injection, 12 months post injection]
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Change in associate biomarkers as compared to placebo in peripheral blood plasma/serum
Time Frame: screening, 14 days post-injection, 30 days post injection, 3 months post injection, 6 months post injection, 12 months post injection
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Immunoassays for Biomarker assessment from blood serum.
Analytes will be measured via immunoassays.
The following analytes will be measured and reported in pg/ml.
IL-1b, IL-6, IL-15, IL-1a, IL-1Ra, IL-7, IL-8, MCP-1, TNF-a , RANTES, VEGF, IFN-g, GRO, IP10, Eotaxin, PDGF-AA, PDGFAB-BB, EGF, FLT3L, GDF15, GDF11, FGF21, IL-18, SOST, OC, FGF-23, PTH, Leptin, Insulin, TIMP1, TIMP2, TGF-b1, TGF-b2, MMP-1, MMP-2, MMP-9, MMP-10, HA, COMP, CS846, CRP.
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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
Time Frame: 32 days post baseline, 6 months post injection, 12 months post injection
|
Immunoassays for CTX-II detection in urine reported as pg/ml
|
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)
Time Frame: screening, 14 days post-injection, 30 days post injection, 3 months post injection, 6 months post injection, 12 months post injection
|
Flow Cytometry based detection and quantification of senescent PBMCs isolated from whole blood.
Intensity of the fluorescent marker C12FDG will be measured.
Cells positive for C12FDG will be quantified and designated as senescent.
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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
Time Frame: 32 days post baseline, 6 months post injection, 12 months post injection
|
Synovial Fluid Analysis
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32 days post baseline, 6 months post injection, 12 months post injection
|
Characterization of Bone Marrow Derived Aspirate Concentrate cell content prior to injection
Time Frame: 32 days post baseline
|
BMAC Analysis
|
32 days post baseline
|
Characterization of Bone Marrow Derived plasma biomarkers prior to injection
Time Frame: 32 days post baseline
|
BMAC Analysis
|
32 days post baseline
|
Change in time to conversion to alternative treatment
Time Frame: 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)
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Alternative procedure as indicated.
The time to resort to alternative therapy from baseline will be recorded
|
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)
|
Collaborators and Investigators
Investigators
- Principal Investigator: Johnny Huard, PhD, Steadman Philippon Research Institute
- Principal Investigator: Marc Philippon, MD, Steadman Philippon Research Institute
- Principal Investigator: Scott L Tashman, PhD, Steadman Philippon Research Institute
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2020-15
- 1UG3AR077748-01 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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