Efficacy, Safety, and Tolerability of Intra-Articular LNA043 in Patients with Symptomatic Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate **knee structural changes** from baseline in the central medial tibiofemoral compartment (cMTFC) of LNA043 compared with placebo in the target knee at Week 104. This is clinically relevant as it aims to assess the potential of LNA043 in modifying the structural progression of knee osteoarthritis, which could lead to improved management of the disease.

Secondary objectives include:

• Evaluating changes from baseline in osteoarthritis pain in the target knee of LNA043 compared with placebo at Week 104.
• Assessing changes from baseline in physical function of LNA043 compared with placebo at Week 104.
• Evaluating structural changes from baseline in the total, medial, and lateral tibiofemoral compartments in the target knee of LNA043 compared with placebo at Week 104.
• Assessing changes from baseline in performance-based physical function assessment of LNA043 compared with placebo at Week 104.
• Evaluating structural progression in the target knee of LNA043 compared with placebo using imaging techniques.
• Assessing the safety and tolerability of the various LNA043 regimens.

The clinical trial involves a total of **331 participants** diagnosed with **osteoarthritis**. The study population comprises both males and females aged between 40 and 75 years. Participants were selected based on specific criteria, including a body mass index (BMI) of less than 40 kg/m² and a diagnosis of primary tibiofemoral knee osteoarthritis according to the standard American College of Rheumatology clinical and radiographic criteria. The trial includes individuals with radiographic disease K-L grade 2 or 3 knee osteoarthritis, with predominantly medial tibiofemoral compartment involvement. Participants were required to have symptomatic osteoarthritis with pain in the target knee for at least six months, and the primary source of pain throughout the body must be due to osteoarthritis in the target knee. The trial population includes a vulnerable population, and lifestyle considerations such as diet and physical activity were not specified in the provided data.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to assess the efficacy, safety, and tolerability of intra-articular regimens of LNA043 compared to placebo in patients with symptomatic knee **osteoarthritis**. The trial is set to span a duration of five years, with an estimated recruitment start date of July 21, 2021, and an anticipated end date of October 25, 2027. Participants will be randomly assigned to receive either LNA043 or a placebo, with the primary objective being to evaluate knee structural changes from baseline in the central medial tibiofemoral compartment at Week 104. Secondary endpoints include changes from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function, cartilage structure, physical function, and the proportion of participants demonstrating structural progression, as well as the assessment of adverse events.

The study will involve a sequence of visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age, body mass index, and specific radiographic and clinical characteristics of knee osteoarthritis. Following the screening, eligible participants will undergo baseline assessments before the commencement of the treatment phase. Follow-up visits will be scheduled at regular intervals to monitor the participants' progress, assess the efficacy and safety of the treatment, and collect data on the primary and secondary endpoints. The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted.

Participant involvement is expected to last for the entire duration of the trial, with the maximum treatment period being 208 weeks. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of the experimental medication **LNA043**, which is a **powder for solution for injection**. This investigational product is developed by Novartis Pharma AG and is intended for **intraarticular use**. The active substance, LNA043, is classified as a protein of other origin. The maximum daily dose of LNA043 is 40 mg, with a total maximum dose of 40 mg over the treatment period. The treatment duration is set for a maximum of 208 weeks. The administration schedule and dosing frequency are designed to evaluate the efficacy, safety, and tolerability of LNA043 in patients with symptomatic knee osteoarthritis.

In this study, a **placebo** is used as the comparator treatment. The placebo is administered in a manner identical to the experimental medication, ensuring the study remains double-blind. The placebo is also provided as a powder for solution for injection and is administered intraarticularly. The use of a placebo allows for a controlled assessment of the effects of LNA043 on knee structural changes in the central medial tibiofemoral compartment over the course of the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. This monitoring is crucial for maintaining the integrity of the study data and for accurately assessing the outcomes related to the investigational product and the placebo. The study is designed to provide comprehensive data on the potential benefits and risks associated with the use of LNA043 in the target patient population.

The efficacy of the investigational product LNA043 in the treatment of symptomatic knee osteoarthritis will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the knee structure, specifically in the central medial tibiofemoral compartment (cMTFC) of the target knee, evaluated at Week 104. Secondary endpoints include changes from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores, changes in cartilage structure, changes in physical function, and the proportion of participants demonstrating structural progression. Additionally, the assessment of adverse events and serious adverse events will be conducted.

Measurements will be collected at specified timepoints throughout the study duration, which spans up to 208 weeks. The WOMAC index, a validated tool, will be utilized to evaluate pain and function, providing a comprehensive assessment of the patient's condition. The study is designed as a randomized, double-blind, placebo-controlled, multi-center trial, ensuring rigorous evaluation of the efficacy of LNA043 compared to placebo. The trial aims to provide robust data on the structural changes in the knee and the overall impact on patient-reported outcomes related to pain and function.