Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis

NCT04815902 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 2020-151UG3AR077748-01
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

Osteoarthritis, Knee

Keywords

Fisetin; Losartan; Osteoarthritis; Knee; Bone Marrow Concentrate; Bone Marrow Aspirate

Outcome Measures

Primary Outcomes (1)

• Incidence of Treatment-Emergent Adverse Events

  Occurrence of adverse events

  Adverse events will be collected from the date of BMAC injection to 12 months after injection

Secondary Outcomes (19)

• 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

Study Arms (4)

Active Fisetin and Active Losartan

EXPERIMENTAL

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).

Drug: Fisetin; Drug: Losartan

Active Fisetin and Losartan Placebo

ACTIVE COMPARATOR

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).

Drug: Fisetin; Drug: Placebo - Losartan

Fisetin Placebo and Active Losartan

ACTIVE COMPARATOR

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).

Drug: Losartan; Drug: Placebo Fisetin

Control

PLACEBO COMPARATOR

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).

Drug: Placebo - Losartan; Drug: Placebo Fisetin

Interventions

Fisetin DRUG

Oral Fisetin 20 mg/kg taken for 10 days total.

Also known as: Novusetin, 7,3',4'-flavon-3-ol, 3,3',4',7-tetrahydroxyflavone

Active Fisetin and Active Losartan; Active Fisetin and Losartan Placebo

Losartan DRUG

12.5 mg oral Losartan taken for 30 days total.

Also known as: Losartan potassium

Active Fisetin and Active Losartan; Fisetin Placebo and Active Losartan

Placebo - Losartan DRUG

Losartan appearance-matched microcrystalline cellulose placebo. 12.5 taken for 30 days total.

Also known as: Placebo Oral Capsule

Active Fisetin and Losartan Placebo; Control

Placebo Fisetin DRUG

Fisetin appearance-matched microcrystalline cellulose placebo. 20 mg/kg taken for 10 days total.

Also known as: Placebo Oral Capsule

Control; Fisetin Placebo and Active Losartan

Eligibility Criteria

• Age: 40 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Steadman Philippon Research Institute: lead
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): collaborator

Study Sites (1)

The Steadman Clinic

Vail, Colorado, 81657, United States

Location

MeSH Terms

Conditions

Osteoarthritis, Knee; Osteoarthritis

Interventions

fisetin; Losartan

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Parallel Assignment

Study Record Dates

• First Submitted: March 17, 2021
• First Posted: March 25, 2021
• Study Start: May 18, 2021
• Primary Completion: February 1, 2025
• Study Completion: June 1, 2025
• Last Updated: April 16, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)