Evaluation of Safety and Tolerability of Intra-Articular Resiniferatoxin and Ropivacaine Hydrochloride in Moderate to Severe Knee Osteoarthritis Pain

The primary objective of this Phase III trial is to assess the **safety** and tolerability of intra-articular injections of RTX-GRT7039 in subjects experiencing moderate to severe pain associated with **osteoarthritis** of the knee. This evaluation is clinically relevant as it aims to determine the potential of RTX-GRT7039 as a therapeutic option for managing pain in osteoarthritis, a condition that significantly impacts patient quality of life and mobility.

Secondary objectives include:

• Assessing the safety of intra-articular RTX-GRT7039 concerning structural changes.
• Investigating the analgesic effectiveness of intra-articular RTX-GRT7039 in both the index knee and non-index knee, if applicable.
• Evaluating the quality of life following treatment with RTX-GRT7039.

The clinical trial involves a total of **204 participants** who are experiencing **moderate to severe pain associated with osteoarthritis of the knee**. The study population includes both male and female subjects, aged **18 years and older**, with a **Body Mass Index (BMI) of 40.0 kg/m² or less**. Participants were selected based on their diagnosis of osteoarthritis of the knee, as per the American College of Rheumatology criteria, and their functional capacity class ranging from I to III. The trial specifically targets individuals who have not achieved sufficient pain relief with the optimal standard of care and for whom further adjustments to pain treatment are not expected to provide additional benefits. The trial population includes a vulnerable group, indicating careful consideration of ethical standards in participant selection. Lifestyle factors such as diet and physical activity were not specified by the sponsor.

The clinical trial is a **Phase III** study designed to evaluate the safety and tolerability of intra-articular injections of **RTX-GRT7039** in subjects experiencing moderate to severe pain associated with **osteoarthritis** of the knee. The trial follows an open-label, single-arm design, where all participants receive the investigational product, RTX-GRT7039, administered via intra-articular injection. The trial is expected to span approximately 78 weeks, with the estimated recruitment start date being August 18, 2022, and the anticipated end date on March 12, 2025.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age (≥ 18 years), body mass index (BMI ≤ 40.0 kg/m²), and a diagnosis of knee osteoarthritis according to the American College of Rheumatology criteria. The screening visit will also assess the functional capacity class (I-III) and document a history of insufficient pain relief with the standard of care. Following successful screening, participants will receive the investigational treatment and attend follow-up visits to monitor safety and efficacy outcomes.

The primary endpoint of the trial is the incidence of treatment-emergent adverse events (TEAEs), including those leading to discontinuation. Secondary endpoints include the incidence of TEAEs representing structural changes in the knee joint, changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and quality of life (QoL) assessments using EQ-5D-5L and SF-36 questionnaires. Participants are expected to remain in the study for the full duration unless they experience adverse events that necessitate early termination or if the investigator deems it in the participant's best interest to withdraw from the study.

The clinical trial involves the administration of **RTX-GRT7039**, a pharmaceutical product formulated as a **concentrate and solvent for solution for injection**. The active substance in RTX-GRT7039 is **resiniferatoxin**, a chemical compound. The medication is administered via **intra-articular injection**. The trial is designed to evaluate the safety and tolerability of RTX-GRT7039 in subjects with moderate to severe pain associated with osteoarthritis of the knee. The maximum treatment period for RTX-GRT7039 is 78 days. The dosing schedule and specific dosage amounts are not explicitly defined in the provided data, indicating that the trial may involve flexible dosing based on individual patient needs or responses.

In addition to RTX-GRT7039, the trial utilizes **Naropin® 5 mg/ml Injektionslösung**, which contains the active substance **ropivacaine hydrochloride**. This product is also administered as a **solution for injection** via the **intra-articular route**. The maximum daily dose of Naropin is 25 mg, with a total maximum dose of 125 mg over the treatment period. The use of Naropin serves as an auxiliary treatment, potentially providing local anesthetic effects to manage pain during the trial. The administration of Naropin is subject to the same 78-day maximum treatment period as RTX-GRT7039. Compliance with the dosing schedule and administration is monitored throughout the trial to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed using several secondary endpoints. The primary focus will be on the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function and pain subscale scores for the index and non-index knee, where applicable. This index is a widely recognized tool for evaluating pain and physical function in patients with osteoarthritis. Additionally, changes in quality of life (QoL) will be measured using the EQ-5D-5L and SF-36 questionnaires, which are validated instruments for assessing health-related quality of life. The incidence of treatment-emergent adverse events (TEAEs) representing structural changes of the knee joint will also be evaluated through imaging methods such as X-ray and magnetic resonance imaging (MRI). These assessments will provide comprehensive data on the efficacy of the intra-articular injections of RTX-GRT7039 in subjects with moderate to severe pain associated with **osteoarthritis** of the knee.