A Trial to Investigate the Safety and Efficacy of Intra-articular 4P004 Injection in Subjects With Knee Synovitis and Osteoarthritis

Exclusion Criteria31

• 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.