Efficacy and Safety Evaluation of Intra-Articular Liraglutide (4P-004) in Patients with Knee Synovitis and Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to assess the **efficacy** of the investigational product 4P004 on **osteoarthritis (OA) pain** in the target knee at Week 4. This is clinically relevant as it aims to provide evidence on the potential of 4P004 to alleviate pain associated with knee synovitis and osteoarthritis, which are common and debilitating conditions affecting joint function and quality of life.

Secondary objectives include: - Evaluating the efficacy of 4P004 on patient-centric data over time, focusing on target knee pain, pain during a nominated pain-aggravating activity (from the WOMAC Pain subscale), symptoms, functional impairment, and global assessment of osteoarthritis. - Assessing the number of responders with respect to OA pain and function. - Evaluating the safety and tolerability of 4P004. These objectives are crucial for understanding the broader impact of 4P004 on patient outcomes and ensuring its safety profile is acceptable for clinical use.

The clinical trial involves a total of **45 participants** diagnosed with **knee synovitis and osteoarthritis**. The study population includes both male and female subjects, aged between 40 and 80 years, who are in general good health, as indicated by a body mass index (BMI) ranging from 18.5 to 35. Participants were selected based on their ability to walk unaided or with the assistance of a cane, and they must have experienced osteoarthritis pain in the target knee for at least six months prior to the study. Additionally, the presence of synovitis in the knee to be treated was confirmed through magnetic resonance imaging (MRI). The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The study aims to assess the efficacy of the investigational product, 4P004, on osteoarthritis pain in the target knee at Week 4.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of the investigational product, 4P-004, in subjects with **knee synovitis and osteoarthritis**. The trial aims to assess the efficacy of 4P-004 on osteoarthritis pain in the target knee at Week 4. The study will involve male and female participants aged between 40 and 80 years, with a body mass index between 18.5 and 35, who have experienced knee osteoarthritis pain for at least six months and have synovitis confirmed by magnetic resonance imaging. The trial is expected to commence recruitment on September 15, 2025, and conclude by May 25, 2026.

Participants will be involved in the study for a maximum treatment period of one month, with the primary endpoint being the change from baseline at Week 4 in the weekly average of target knee daily pain intensity using the WOMAC Pain subscore. Secondary endpoints include changes from baseline at various weeks in pain scores, patient global assessment, and the incidence and severity of treatment-emergent adverse events. The study will also monitor clinical laboratory assessments, vital signs, and conduct directed physical examinations.

The sequence of study visits includes an initial screening visit to determine eligibility based on the inclusion criteria. Following randomization, participants will attend follow-up visits at Weeks 2, 4, 6, 8, 10, and 12 to assess efficacy and safety parameters. The end-of-study visit will occur at Week 12, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure participant safety and data integrity.

The clinical trial involves the administration of **4P-004**, a solution for injection, as the experimental medication. The active substance in 4P-004 is **liraglutide**, a protein-based compound. The pharmaceutical form of 4P-004 is a solution for injection, and it is administered via **intra-articular injection**. The maximum daily dose is 2 mg, with a total maximum dose of 2 mg over the treatment period. The treatment period is limited to one week. The administration of 4P-004 is conducted under controlled conditions to ensure participant safety and adherence to the dosing schedule. Compliance with the dosing regimen is monitored throughout the trial to ensure accurate assessment of the medication's efficacy and safety.

The trial also includes a non-experimental treatment, which is a **0.9% w/v Sodium Chloride Injection BP** serving as the placebo. This solution is used as a comparator to evaluate the efficacy of the experimental medication. The placebo is administered in the same manner as the experimental treatment, via intra-articular injection, to maintain the double-blind nature of the study. The use of a placebo is critical in distinguishing the effects of the experimental medication from psychological or other non-specific effects. Participant compliance with the placebo administration is similarly monitored to ensure the integrity of the trial results.

The efficacy of the investigational product, 4P004, in the treatment of knee **osteoarthritis** and synovitis will be assessed through a multicenter, randomized, double-blind, placebo-controlled trial. The primary endpoint for evaluating efficacy is the change from baseline at Week 4 in the weekly average of target knee (TK) daily pain intensity, measured using the WOMAC Pain subscore. Secondary endpoints include changes from baseline at Weeks 2, 6, 8, 10, and 12 in the weekly average of TK daily pain, as well as changes in the NRS (0-10) pain score during a nominated pain-aggravating activity, WOMAC subscores and total score, and the Patient Global Assessment of OA (PGA-OA). Additionally, the percentage of OMERACT-OARSI responders will be evaluated at Weeks 2, 4, 8, and 12.

Data collection will involve patient-reported outcomes and clinical assessments at specified timepoints throughout the trial. The incidence and severity of treatment-emergent adverse events (TEAEs) will also be monitored, alongside clinical laboratory assessments, vital signs, and directed physical examinations. These measures will provide a comprehensive evaluation of the efficacy and safety of 4P004 in the target population.