This phase 2a trial is an international, multicenter, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of one single intra-articular (IA) injection of 4P004 or placebo in:

• patients between 40 and 80 years of age,
• with synovitis and grade 2 to 4 osteoarthritis (OA) of the knee according to Kellgren and Lawrence (KL) classification.

Inclusion Criteria:

• Participants who have the capacity to give informed consent and who are willing to comply with all trial related procedures and assessments.
• Participants between 40 and 80 years of age.
• Female participant of childbearing potential (defined as any woman unless postmenopausal for at least one year or surgically sterile) must use highly effective methods of contraception as defined in the protocol. Highly effective contraceptive measures must be continued throughout the trial until the final visit.
• Bodyweight > 40 kg.
• Body mass index (BMI) ≥ 18.5 and ≤ 35.
• Ambulatory (single assistive devices such as canes allowed).
• Widespread Pain Index (WPI) ≤ 4.
• Pain NRS (0-10) < 4 in the contralateral knee.
• History of OA-related pain of the TK for at least 6 months.
• Moderate to severe pain of the TK the majority of days during the last 3 months as per participant's judgement.
• Moderate to severe pain of the TK on the WOMAC Pain subscale prior to the Randomization visit (V2) complying with: a) Complete WOMAC Pain diary for at least 7 of the last 10 days prior to V2 (including V2/D1 rating which is mandatory), and b) Diary reported WOMAC Pain between 5 and 9 for at least 7 of the last 10 days.
• History of insufficient pain relief, intolerance, or contraindication to NSAIDs, and at least a history of insufficient pain relief from at least one of the following therapies: a) Acetaminophen/paracetamol, b) Opioids including tramadol, or c) Corticosteroids, hyaluronate IA injections (efficacy less than 3 months according to the patient).
• KL grade 2 to 4 on the Schuss radiograph.
• Predominant femorotibial OA based on the OA Research Society International. (OARSI) Atlas reading (Altman & Gold, 2007).
• Presence of synovitis in the TK assessed locally using PDUS, and synovial thickness of ≥ 5 mm evaluated through a longitudinal view of the suprapatellar pouch and axial views of the medial and lateral patellofemoral pouches.
• Negative urine drug screen (performed locally): amphetamines, barbiturates, cocaine.
• CE-MRI Central reading to confirm synovitis with a synovial Semi-Quantitative (SQ) ≥ 9 or a SQ score ≥7 with at least one site with a score ≥ 2.

Exclusion Criteria:

• Pregnant or breastfeeding women.
• Significant malalignment of anatomical axis (medial angle formed by the femur and tibia) of the TK (varus > 10°, valgus > 10°) by radiography.
• Secondary OA such as joint dysplasia, aseptic osteonecrosis, joint infection, acromegaly, Paget disease, hemochromatosis, joint crystal disease or any inflammatory joint disease.
• Any known active infections including skin infections at the site injection or increased predisposition for the development of infections.
• Any partial knee replacement of the TK.
• Acute fracture or IA trauma to the TK within 12 months prior to the screening visit.
• Major knee surgery performed within the previous 12 months or planned during the trial.
• Arthroscopy of the TK within 6 months prior to the screening visit.
• Presence of any painful conditions that could confound accurate assessment of pain from OA in the TK, such as fibromyalgia, peripheral neuropathy or vascular insufficiency.
• Treatment with systemic corticosteroids (other than IA) at a dose greater than 10 mg prednisone or the equivalent per day for more than 7 days within 4 weeks prior to the screening visit.
• Treatment of the TK with any IA injection (including corticosteroids, hyaluronic acid derivatives, Platelet Rich Plasma….) within 24 weeks prior to the screening visit.
• Any treatment with glucosamine, chondroitin sulfate, or other nutraceuticals with potential activity on OA within the previous 3 months prior to the screening visit.
• Treatment with duloxetine for OA (allowed if given for depressive disorders at stable dose since at least 3 months before V1).
• Any significant psychiatric illness unless well controlled since at least 6 months.
• Current treatment with combination of insulin and liraglutide (Xultophy®) or with GLP-1 agonist administered once a week (semaglutide, dulaglutide).
• High-risk of bleeding.
• Congestive Heart Failure stage III or IV in the New York Heart Association classification.
• History or current diagnosis of electrocardiogram ECG abnormalities indicating significant safety risk (such as ischemia, significant cardiac arrhythmias).
• Glycemia < 4.4 mmol/L (or 80 mg/dL) at screening.
• Clinically significant abnormal laboratory test at screening, in particular: haemoglobin <10 g/dL, white blood cell <3000/µL (3.0 Giga/L), absolute neutrophil count <1000/µL (1.0 Giga/L), platelets count <100,000/µL (100 Giga/L), alanine aminotransferase or aspartate aminotransferase >2.5 upper limit of normal (ULN), total bilirubin >1.5 ULN, lipasemia >1 ULN.
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, using Chronic Kidney Disease - EPIdemiology (CKD EPI) 2021 Formula.
• Any other abnormal laboratory results that the Investigator believes should preclude the subject's participation in the trial.
• History of hypersensitivity to IMP or excipients (liraglutide or disodium phosphate dihydrate, propylene glycol, phenol).
• Any contraindication for MRI (cardiac pacemaker, deep brain stimulators, intraocular metal, cerebral aneurysm clips, recent stents, cochlear implants, neurostimulators and implantable pumps) or inability to undergo MRI (e.g., body size, leg not fitting in the coil, claustrophobia).
• History of hypersensitivity reactions to a gadolinium-based contrast agent.
• Any CE-MRI Central reading additional diagnoses: posterior meniscal root tears, subchondral insufficiency fractures, osteonecrosis, malignant bone marrow infiltration, solid tumours, and traumatic fracture or bone bruise using ROAMES (Roemer et al., 2020).
• Previous participation in clinical research with a disease-modifying OA drug during the last 2 years.
• Participation in an interventional clinical research trial within 3 months before screening.
• Participants who, in the investigator's judgement, are at risk of falling.
• Participants with a history, or current diagnosis, of pancreatitis, thyroid cancer (including medullary thyroid carcinoma), multiple endocrine neoplasia type-2 (MEN2), diabetic ketoacidosis, type-1 diabetes mellitus (T1DM), inflammatory bowel disease, or diabetic gastroparesis.
• Participants currently, or within the last 10 days, taking any anticoagulant treatment.