Efficacy and Safety Comparison of SRSD107 and Enoxaparin in Preventing Venous Thromboembolism in Elective Unilateral Total Knee Arthroplasty

The primary objective of this study is to evaluate the **efficacy** of different dose levels of SRSD107 in subjects undergoing elective, primary, unilateral total knee arthroplasty (TKA), comparing SRSD107 to enoxaparin. This is clinically relevant as it aims to determine the potential of SRSD107 in preventing **venous thromboembolism**, a significant complication following TKA, thereby potentially offering an alternative to the current standard treatment with enoxaparin.

Secondary objectives include:

• Evaluating the **safety** of different dose levels of SRSD107 in the same patient population, comparing SRSD107 to enoxaparin. This is crucial for understanding the risk profile and ensuring patient safety when considering SRSD107 as a therapeutic option.
• Assessing the **efficacy** of different dose levels of SRSD107, further comparing it to enoxaparin, to provide comprehensive data on its therapeutic potential and effectiveness in preventing venous thromboembolism events.

The clinical trial involves participants diagnosed with **venous thromboembolism** who are undergoing elective, primary, unilateral total knee arthroplasty. The study population includes both male and female subjects, aged between 60 and 85 years, with a body mass index ranging from 18.0 to 35.0 kg/m². Participants are required to be in general good health, as indicated by normal activated partial thromboplastin time, prothrombin time, and international normalized ratio at screening. The trial does not include a vulnerable population. Participants were selected based on their eligibility to undergo the specified surgical procedure under general anesthesia and their willingness to comply with study requirements, including medication adherence and follow-up visits. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **randomized**, open-label, blinded endpoint evaluation, active-controlled study to assess the efficacy and safety of **SRSD107** compared to **enoxaparin** in adult subjects undergoing elective primary unilateral total knee arthroplasty. The trial is set to commence recruitment on July 1, 2025, and is expected to conclude by December 7, 2026. The study will involve multiple visits, starting with a screening visit to confirm eligibility based on criteria such as age, body mass index, and coagulation parameters. Participants will be required to provide written informed consent prior to any study-related procedures.

The trial will include a pre-surgical period where participants will receive the study drug for at least 28 days prior to surgery. The primary endpoint is the incidence of total **venous thromboembolism** events, including deep vein thrombosis and pulmonary embolism, assessed through venography performed approximately 12 days post-surgery. Secondary endpoints will evaluate bleeding events and adverse events throughout the study duration. Participants will be monitored through follow-up visits, including a venography visit 10-14 days post-surgery, and additional assessments on Day 64 and Day 169.

Participant involvement is expected to last until the end-of-study visit, with conditions for early termination including non-compliance with study requirements or withdrawal of consent. The trial will adhere to rigorous methodological standards to ensure the reliability and validity of the findings, contributing valuable data on the comparative efficacy and safety of SRSD107 and enoxaparin in preventing venous thromboembolism in the specified surgical context.

The clinical trial involves the administration of **SRSD107 Injection**, an experimental medication developed by Sirius Therapeutics Inc. This pharmaceutical product is formulated as an **injection** and is administered via the **subcutaneous route**. The active substance, SRSD107, is derived from nucleic acid. The maximum daily dose for SRSD107 is 600 mg, with a total treatment period of one day. The dosing schedule is designed to ensure optimal efficacy and safety, and participant compliance will be monitored throughout the trial.

In addition to the experimental treatment, the study includes a **comparator treatment** using **Clexane 4.000 I.E. (40 mg)/0.4 ml Injektionslösung in einer Fertigspritze**, which contains the active substance **enoxaparin sodium**. This comparator is a solution for injection, also administered subcutaneously. The maximum daily dose for enoxaparin sodium is 40 mg, with a treatment period extending up to 14 days. The comparator serves to evaluate the efficacy and safety of SRSD107 against a well-established anticoagulant therapy.

A **placebo** control is also utilized in the form of a **0.9% sodium chloride solution for injection**. This solution is used to maintain the study's integrity by providing a baseline for comparison against the active treatments. The placebo is administered in a manner consistent with the other study medications, ensuring blinding and unbiased assessment of outcomes.

The efficacy of the clinical trial will be assessed by evaluating the incidence of total **venous thromboembolism (VTE)** events. This includes deep vein thrombosis (DVT), both asymptomatic confirmed by venography and objectively confirmed symptomatic, non-fatal and fatal pulmonary embolism (PE), and unexplained death for which PE cannot be excluded. The primary endpoint will be measured from the date of surgery through the venography visit, which is scheduled to occur 12±2 days post-surgery.

Secondary endpoints will include the incidence of a composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) from the pre-surgical period through the venography visit. Additionally, the incidence of a composite of MB, CRNMB, and any bleeding, including minor bleeding events, will be assessed through the venography visit, Day 64, and Day 169, respectively. The incidence of adverse events (AEs) throughout the study will also be monitored. Furthermore, the incidence of major VTE, defined as objectively confirmed symptomatic DVT and PE, asymptomatic proximal DVT (confirmed by venogram), fatal PE, and unexplained death for which PE cannot be excluded, will be evaluated from the date of surgery through the venography visit and Day 64.