Evaluation of Genicular Arteries Embolization Using Ioversol and Ethyl Esters of Iodised Fatty Acids in Symptomatic Knee Osteoarthritis

The primary objective of this study is to assess the efficacy of **Genicular Arteries Embolization (GAE)** using an ethiodized oil-based emulsion compared to a sham procedure. This is evaluated by comparing the effect on knee pain at 3 months in patients with symptomatic **knee osteoarthritis**. This objective is clinically relevant as it aims to determine the potential of GAE as a therapeutic intervention for reducing knee pain, which is a significant symptom impacting the quality of life in patients with knee osteoarthritis.

Secondary objectives include:

• Knee pain assessment using the VAS pain score at 1, 6, and 12 months post-randomization.
• Patient's global health assessment at 1, 3, 6, and 12 months post-randomization.
• Evaluation of the patient's WOMAC index and sub-scales (knee pain, function, and stiffness) at 1, 3, 6, and 12 months post-randomization.
• Assessment of the patient's KOOS index and sub-scales (knee pain, function, symptoms, sport, quality of life, and stiffness) at D0 and 3 months post-randomization.
• Evaluation of the patient's HAD index and sub-scales (anxiety and depression) at D0 and 3 months post-randomization.
• Semi-quantitative MRI assessment of knee osteoarthritis of the target knee at 6 months.
• Assessment of pain medication usage at 1, 3, 6, and 12 months post-randomization.
• Evaluation of non-pharmacological treatments at 1, 3, 6, and 12 months.
• Identification of responder patients according to the OMERACT-OARSI set of responder criteria at 3, 6, and 12 months.
• Determination of patients reaching an acceptable symptom state (PASS) at 3, 6, and 12 months.
• Monitoring the occurrence of adverse events and serious adverse events at 1, 3, 6, and 12 months.
• Observation of events of interest in the target knee in both groups at 6 and 12 months.
• Evaluation of the incremental efficiency of GAE compared to sham treatment.

The clinical trial focuses on patients with **knee osteoarthritis**, aiming to assess the efficacy of a specific treatment. The study population includes both male and female participants, aged between 40 and 90 years, who have been diagnosed with primary knee osteoarthritis according to the American College of Rheumatology classification. Participants must have a radiographic Kellgren and Lawrence score of 2 or higher and a Visual Analog Scale (VAS) pain score of at least 40 mm. The trial excludes individuals eligible for knee surgery and requires a previous intra-articular injection in the target knee. Women of childbearing potential must have a negative beta-HCG test before randomization. Participants must be affiliated with social security, have signed informed consent, and possess a good understanding of the French language. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **sham-controlled**, **double-blind**, multicenter study to evaluate the efficacy of Genicular Arteries Embolization (GAE) using an ethiodized oil-based emulsion in patients with symptomatic **knee osteoarthritis**. The primary objective is to assess the change in knee pain over a period of three months, as measured by the Visual Analogue Scale (VAS). The trial is expected to commence recruitment on June 7, 2024, and conclude by June 7, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (40-90 years), previous intra-articular injection, and a diagnosis of primary knee osteoarthritis according to the American College of Rheumatology classification. The screening will also ensure a VAS pain score of at least 40 mm and that participants are not eligible for knee surgery. Women of childbearing potential must have a negative beta-HCG test before randomization.

Following the screening, eligible participants will be randomized to receive either the GAE procedure or a sham procedure. The primary endpoint will be evaluated at three months post-randomization, with secondary endpoints assessed at 1, 6, and 12 months. These include changes in VAS pain scores, patient global health assessments, and various osteoarthritis-specific indices such as the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Knee injury and Osteoarthritis Outcome Score (KOOS).

Participants are expected to be involved in the study for a maximum of 12 months, with follow-up visits scheduled at 1, 3, 6, and 12 months post-randomization. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will also monitor the use of pain medication, non-pharmacological treatments, and any adverse events throughout the study duration.

The clinical trial involves the administration of **Optiray 300**, a solution for injection containing **ioversol** as the active substance. This pharmaceutical form is a solution injectable en flacon, with a concentration of 300 mg I/mL. The administration route is intraarterial, with a maximum daily and total dose of 2 mL. The treatment period is limited to one day. Optiray 300 is used in conjunction with **Lipiodol Ultra Fluide** for extemporaneous mixing, enhancing its application in the trial.

**Lipiodol Ultra Fluide** is another investigational product in this trial, containing ethyl esters of iodised fatty acids from poppyseed oil. It is also a solution for injection, with a concentration of 480 mg/mL. The administration is via intraarterial use, with a maximum daily and total dose of 6 mL, and a treatment period of one day. This product is mixed with Optiray 300 to form an ethiodized oil-based emulsion for the trial.

**Xylocaine 5 mg/mL Sans Conservateur** is used as an auxiliary treatment. It contains anhydrous lidocaine hydrochloride as the active substance. This solution for injection is administered subcutaneously, with a maximum daily and total dose of 200 mg. The treatment period is one day. Xylocaine serves as a local anesthetic to facilitate the procedure.

**Heparine Choay 5,000 UI/1 mL** is another auxiliary treatment, containing **heparin sodium**. This solution for injection is administered intravenously, with a maximum daily and total dose of 50 IU/kg. The treatment period is one day. Heparine Choay is used to prevent clot formation during the procedure.

**Visipaque 320 mg d’I/mL** is also included as an auxiliary treatment. It contains **iodixanol** and is a solution for injection administered intraarterially. The maximum daily and total dose is 100 mL, with a treatment period of one day. Visipaque is used as a contrast agent to enhance imaging during the procedure.

Efficacy in the clinical trial titled "LIPIOJOINT-2: A randomized sham-controlled, double-blind, multicenter trial on the effect of Genicular Arteries Embolization in symptomatic knee osteoarthritis" will be assessed primarily through the change in the Visual Analogue Scale (VAS) pain score. The primary endpoint is defined as the change in the VAS pain score between randomization and 3 months, measured on a scale from 0 (No Pain) to 100 (Worst Possible Pain). Secondary endpoints include changes in the VAS pain score at 1, 6, and 12 months post-randomization, as well as changes in the patient's global health assessment using the VAS of the EQ-5D questionnaire at 1, 3, 6, and 12 months.

Additional secondary endpoints involve the assessment of the Western Ontario and McMaster Universities Arthritis Index (WOMAC) total score and sub-scores (pain, function, stiffness) at 1, 3, 6, and 12 months, and the Knee injury and Osteoarthritis Outcome Score (KOOS) total and sub-scores at Day 0 and 3 months. The Hospital Anxiety and Depression (HAD) scale will also be evaluated at Day 0 and 3 months. Semi-quantitative MRI scoring, including the Whole-Organ Magnetic Resonance Imaging Score (WORMS), Knee Osteoarthritis Scoring System (KOSS), Boston-Leeds Osteoarthritis Knee Scoring (BLOKS), and MRI Osteoarthritis Knee Score (MOAKS), will be conducted at 6 months.

Other parameters include the description of pain medication and non-pharmacological treatments at 1, 3, 6, and 12 months, the number of responder patients under the OMERACT-OARSI definition at 3, 6, and 12 months, and the number of patients reaching an acceptable symptom state at these timepoints. Adverse events (AE) and serious adverse events (SAE) will be documented at 1, 3, 6, and 12 months, along with the number of events in the target knee, including intra-articular injection, Genicular Arteries Embolization (GAE), and knee surgery at 6 and 12 months. A medico-economic study will assess the incremental cost-utility ratio.