Evaluation of Rivaroxaban Versus Low-Molecular-Weight Heparin for Thromboembolism Prevention in High-Risk Patients with Lower Limb Trauma Requiring Immobilization

The primary objective of the RIVACAST study is to demonstrate the **non-inferiority** of **Rivaroxaban** compared to low-molecular weight heparin (LMWH) in the primary prevention of symptomatic thromboembolic events in patients with lower limb trauma requiring orthopaedic immobilisation. These patients are considered high-risk for venous thromboembolism (VTE) as determined by a TRiP(cast) score of 7 or higher. This objective is clinically relevant as it seeks to establish an effective alternative to LMWH, potentially offering a more convenient oral administration route with **Rivaroxaban** for patients undergoing immobilisation due to lower limb trauma.

The clinical trial involves participants with **lower limb trauma** requiring immobilization, aiming to assess the non-inferiority of Rivaroxaban compared to LMWH in preventing symptomatic thromboembolic events. The study population includes both male and female subjects aged 18 years and older, who have consulted in one of the participating emergency departments. Participants are required to have a TRiP(cast) score of 7 or higher, indicating a high risk of venous thromboembolism (VTE), and must have an intended duration of orthopaedic immobilization of at least two weeks. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. All participants must have full insurance coverage and provide signed and dated informed consent. Lifestyle factors such as diet and physical activity are not specified as part of the study criteria.

The clinical trial is designed to evaluate the **non-inferiority** of **Rivaroxaban** compared to low-molecular-weight heparin (LMWH) in preventing symptomatic thromboembolic events in patients with lower limb trauma requiring immobilization. This is a randomized, double-blind, controlled trial with a primary endpoint of assessing the rate of symptomatic venous thromboembolic events, including deep venous thrombosis, pulmonary embolism, and death due to pulmonary embolism, within 45 days post-inclusion. The trial is expected to commence recruitment on June 3, 2024, and conclude by September 3, 2026, with a maximum treatment period of 50 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), lower limb injury requiring immobilization, and a TRiP(cast) score of ≥7. Following the screening, participants will be randomized to receive either **Rivaroxaban** or one of the LMWHs, such as **Nadroparin Calcium**, **Dalteparin Sodium**, **Enoxaparin Sodium**, or **Tinzaparin Sodium**, administered via subcutaneous injection, or **Rivaroxaban** administered orally. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will assess the primary endpoint and gather final data on the participants' health outcomes.

The expected length of participant involvement is up to 50 days, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and are fully insured throughout the study duration.

The clinical trial involves the administration of several **experimental medications** and a **comparator treatment**. The primary experimental medication is **Xarelto** (rivaroxaban), which is provided in the form of 10 mg film-coated tablets. The route of administration is oral, with a maximum daily dose of 10 mg. The treatment period is set for a maximum of 50 days. Participant compliance with the oral administration is monitored through regular follow-ups and pill counts.

**FRAXIPARINE** (nadroparin calcium) is used as a comparator treatment in two different dosages: 3,800 U.I. Axa/0.4 ml and 5,700 U.I. Axa/0.6 ml. Both are solutions for injection provided in pre-filled syringes. The administration route is subcutaneous injection, with maximum daily doses of 3,800 and 5,700 anti-Xa IU, respectively. The treatment period is up to 50 days, and compliance is monitored through injection logs maintained by healthcare providers.

**FRAGMINE** (dalteparin sodium) is also used as a comparator treatment, available in two dosages: 2,500 U.I. anti-Xa/0.2 mL and 5,000 U.I. anti-Xa/0.2 mL. These are solutions for injection in pre-filled syringes, administered subcutaneously. The maximum daily doses are 2,500 and 5,000 anti-Xa IU, respectively, with a treatment period of up to 50 days. Compliance is ensured through healthcare provider-administered injections.

**Inhixa** (enoxaparin sodium) is provided as a 4,000 IU (40 mg)/0.4 mL solution for injection in pre-filled syringes. The administration is via subcutaneous injection, with a maximum daily dose of 4,000 anti-Xa IU. The treatment period is up to 50 days, and compliance is monitored through healthcare provider records.

**INNOHEP** (tinzaparin sodium) is administered as a 4,500 UI anti-Xa/0.45 ml solution for injection in pre-filled syringes. The route of administration is subcutaneous injection, with a maximum daily dose of 4,500 anti-Xa IU. The treatment period is up to 50 days, with compliance monitored through injection logs.

**LOVENOX** (enoxaparin sodium) is provided as a 4,000 UI (40 mg)/0.4 ml solution for injection in pre-filled syringes. It is administered subcutaneously, with a maximum daily dose of 4,000 anti-Xa IU. The treatment period is up to 50 days, and compliance is monitored through healthcare provider records.

All medications are administered under the supervision of healthcare professionals, ensuring adherence to dosing schedules and monitoring for any adverse effects. The trial aims to evaluate the non-inferiority of rivaroxaban compared to low-molecular-weight heparins in preventing thromboembolic events in patients with lower limb trauma requiring immobilization.

Efficacy in the clinical trial titled "RIVACAST - RIVAroxaban versus low-molecular weight heparin in patients with lower limb trauma requiring brace or CASTing" will be assessed by evaluating the primary endpoint, which is the rate of symptomatic venous thromboembolic events. These events include deep venous thrombosis, pulmonary embolism, and death due to pulmonary embolism, occurring within 45 days after inclusion in the study. The trial aims to demonstrate the non-inferiority of **Rivaroxaban** compared to low-molecular weight heparin (LMWH) in the primary prevention of these thromboembolic events in patients with orthopaedic immobilisation for lower limb trauma, who are considered high-risk for venous thromboembolism (VTE) based on a TRiP(cast) score of 7 or higher.