Knee osteoarthritis (KOA) is a leading cause of chronic pain and disability among Veterans, which contributes significantly to reduced mobility, impaired quality of life, and increased health care utilization. First-line therapies, including non-steroidal anti-inflammatory drugs, physical therapy, and intra-articular corticosteroids, provide modest and short-term relief, while being associated with other side effects (i.e., potential for hastened cartilage loss) and no disease-modifying potential. Total knee arthroplasty, although effective, is not suitable for all patients and carries surgical risks. There is an unmet need for effective, durable, and locally-targeted therapies that can alleviate pain and improve function. The development of new therapies for this condition is thus a priority for the VA.

While the therapy has been used in humans in other contexts, to date there are no data on the safety, feasibility, and potential efficacy of intra-articular IC14 administration in patients with KOA. A small-scale, Phase I "first-in-joint" pilot and feasibility trial is therefore critical to inform the design and implementation of larger, definitive studies. Specifically, preliminary data are needed to (1) determine the appropriate inclusion/exclusion criteria, (2) solidify the study design and study processes,(3) assess patient tolerance and acceptability of i.a. mAb injection, (4) evaluate safety profiles of the localized biologic intervention. Participants will be randomized into one of three arms, (a placebo arm, a low-dose arm, and a high-dose arm) and will be followed to evaluate the safety and feasibility of this treatment.

In recent years, pain in osteoarthritis has been tied to inflammation in the joint. For example, Philpott et al. found that, among 258 patients with KOA, moderate to severe synovitis on ultrasound was associated with a 2- to 4-fold increase in the risk of constant and intermittent pain. A prior study in 535 patients from the Multicenter Osteoarthritis Study (MOST) cohort found that the presence of synovitis on contrast-enhanced magnetic resonance imaging (MRI) was associated with a 9-fold increase in the risk of pain. Supporting these cross-sectional associations is the observation that corticosteroid injections, the use of which aims to reduce inflammation, have been a mainstay of treatment for years, though studies estimating these benefits are heterogeneous and suggest only modest effects 8,9. In addition to contributing to pain, synovitis is likely to contribute to the deterioration in joint structures including the progression of cartilage loss.10,11 For example, a recent study from the Osteoarthritis Initiative demonstrated that sustained synovitis on MRI was associated with more rapid structural progression over 4 years.

Despite evidence that synovitis plays a role in the symptoms and progression of the disease, to date, highly effective therapies to reduce pain in osteoarthritis by reducing synovitis have not been developed. This may be, in part, due to the complex nature of osteoarthritis pain as well as the lack of strong pathophysiologic rationale for prior therapies. For example, a number of trials evaluated the benefit of blocking Interleukin(IL)-1, with heterogeneous results suggesting small benefits.12

CD14 is a pattern-recognition co-receptor of the innate immune response that plays a critical role in mediating inflammatory responses to damage-associated molecular patterns (DAMPs) present in osteoarthritic joints. In KOA, receptors like CD14 contribute to DAMP-activation of synovial macrophages which drive chronic low-grade inflammation through the release of pro-inflammatory cytokines, such as IL-1β and TNF-α. These cytokines in turn sensitize nociceptors contributing to pain, and promote chondrocyte production of degradative enzymes accelerating joint degeneration. By blocking CD14, it may be possible to reduce macrophage activation and downstream inflammatory cascades within the knee, thus reducing symptoms and potentially affecting structural progression. Indeed, the investigators' published data in the murine destabilization of the medial meniscus (DMM) OA model suggests that deficiency of CD14 leads to reduced synovial cytokine expression after injury, mitigates development of pain-related behavior, and reduces cartilage loss.17 Thus, targeting CD14 represents a novel, mechanism-based approach to modulate synovial inflammation, potentially offering symptom relief with fewer side effects compared to traditional therapies. Fortunately, a neutralizing mAb against human CD14 (IC14) already exists and has extensive pre-clinical and in-human safety data from prior work in other conditions.15,16 Implicit Bioscience is preparing an IND submission for intra-articular use of IC14 in OA for this study. Further, the "first-in-human" studies have been performed (for systemic use) and have shown no serious safety concerns that would preclude further study.

This trial would represent the first human study of this novel injectable therapeutic agent. The goal of this 2-year study is to establish feasibility and initial safety of intra-articular injection with the goal of informing the design of a Merit-funded multi-site Phase II study to establish biologic efficacy and evaluate safety within the VA network.

The central study team includes experts in clinical epidemiology and clinical trials, rehabilitation medicine, osteoarthritis, and rheumatology at the VA. Joshua Baker is an Associate Professor of Medicine and Epidemiology at the Hospital of the University of Pennsylvania and the CMCVAMC. He is a VA-funded investigator with an interest in obesity, muscle loss, physical functioning, and long-term outcomes in patients with common forms of arthritis. He is the Clinical Core 3 Co-Leader of the CReATE Motion Center, the Co-Director of the local Network of Dedicated Enrollment Sites (NODES) program, and Director of the Clinical Research Center at the CMCVAMC. He has served as the national PI for 2 RDT-funded trials including the MOVE-OK trial and the ongoing ReAKTIV trial. He has also served as a local site investigator (LSI) for several VA-funded clinical trials.

The CReATE Motion center was recently funded by VA RDT with the goal of promoting the more rapid translation of highly promising new therapeutics that have the potential to improve the lives of Veterans with osteoarthritis. Dr. Baker is the Director of the Clinical Core, which can provide project manager and research coordinator effort for center-related studies. In addition to this support, the center provides institutional knowledge and experience with clinical studies in KOA, including the ability to generate recruitment lists, organize off-site testing (e.g. MRI), contribution to screening and recruitment, and oversight of data integrity. These resources will be leveraged as part of this protocol.

The study is a randomized trial with 2 active dose levels (30 patients, randomized 1:1:1) with a 16-week follow-up. Patient-reported outcomes will be assessed at 2-week intervals and safety as well as physical functioning assessed and blood draws performed at in-person visits at month 1 and 3. Participants may also have synovial fluid removed from their knee at in-person visits. Participants will undergo a non-contrast MRI scan before randomization and administration of the study drug or placebo. They will also receive another MRI at 3 months. The investigators aim to randomize 30 Veterans within 18 months.

In this currently proposed study, the highest dose the investigators will use will be 5 mL of 20 mg/mL IC14 drug (thus, 100 mg, which for a 70 kg patient will be 1.4 mg/kg). The investigators will use 100 mg and 40 mg as the doses for the high and low dose groups and compare to a control of saline only (0 mg). The syringes will be masked by the research pharmacist.

Participants will be monitored by study investigators and an independent data safety monitoring officer (DSMO) will be identified. The study will include regular clinical assessments, with moderate to severe events resulting in a pause to further randomizations after discussion with the IRB. A Data and Safety Monitoring Plan (DSMP) will be generated and approved by the DSMO. Standard procedures for medical emergencies will be followed. All adverse events will be reported to the IRB and applicable regulatory bodies in accordance with federal regulations.

There is no guarantee of direct benefit to participants. However, participants may benefit from increased clinical monitoring. The knowledge gained from this trial may benefit future patients by improving the understanding of CD14-targeted therapies and their safety profiles.

Inclusion Criteria:

• ACR Classification Criteria for Knee Osteoarthritis
• Pain >=5 on Visual Analogue Scale
• Kelgren-Lawrence Grade >1
• Joint Effusion on Exam
• Able to provide informed consent

Exclusion Criteria:

• Serious or hospitalized infection in last 1 year
• Poorly controlled crystal arthritis in last 6 months
• Pain Pressure Threshold (PPT) testing <=3
• History of diagnosed fibromyalgia
• Receipt of corticosteroid in affected knee within 3 months
• Receipt of visco-supplementation or other intra-articular therapy (other than corticosteroid) within 6 months
• Ongoing participation in another interventional study
• Inability to ambulate without assistive device
• Pregnancy or Lactation
• History of knee arthroplasty in either knee
• Symptomatic heart failure
• Glomerular filtration rate <45
• Class III obesity (BMI>40 kg/m2)
• Recent active malignancy (chemotherapy, radiation, or surgery within 3 months)
• Poorly controlled diabetes (A1c>8%)
• Rheumatoid Arthritis
• Psoriatic Arthritis