Intermediate versus standard dose enoxaparin to prevent venous thromboembolism in severe trauma patients: a multicenter double blind randomised controlled trial (HEPTRAUMA)

The primary objective is to determine the effect of intermediate versus standard dose low-molecular-weight heparin on the incidence of major venous thromboembolism following severe trauma. This objective addresses the critical clinical need to optimize thromboprophylaxis in trauma patients who face elevated thromboembolic risk while balancing the potential for bleeding complications.

The secondary objectives are:

• To evaluate the effect of intermediate versus standard dose low-molecular-weight heparin on the net clinical benefit combining major venous thromboembolism and major bleeding events

• To evaluate the effect of intermediate versus standard dose low-molecular-weight heparin on the incidence of major bleeding and clinically relevant non-major bleeding as per ISTH definition

• To evaluate the effect of intermediate versus standard dose low-molecular-weight heparin on the incidence of major venous thromboembolism and major bleeding at day 30 following randomisation after severe trauma

• To evaluate the effect of intermediate versus standard dose low-molecular-weight heparin on the incidence of deaths at day 30 following randomisation after severe trauma

• To evaluate the effect of intermediate versus standard dose low-molecular-weight heparin on the individual components of the primary outcome

• To evaluate the effect of intermediate versus standard dose low-molecular-weight heparin on the incidence of red blood cell transfusions within 14 days following randomisation after severe trauma or until hospital discharge

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted of **adult patients** aged **18 years and older** who were admitted to an **intensive care unit** following **severe trauma**. Both **male** and **female** subjects were included in the trial. Participants were selected based on an expected ICU stay exceeding 48 hours and a planned administration of **low-molecular-weight heparin**. Eligibility also required affiliation to the French social security system or possession of a European Health Insurance Card. The trial did not involve vulnerable populations. No additional information regarding lifestyle considerations, general health status beyond the trauma condition, or other participant characteristics was provided by the sponsor.

This is a multicenter, double-blind, randomized controlled trial designed to evaluate the efficacy of intermediate dose versus standard dose enoxaparin sodium for the prevention of venous thromboembolism in patients with severe trauma. The trial investigates the use of low-molecular-weight heparin administered via subcutaneous injection as a solution for injection. The study employs a placebo-controlled design utilizing sodium chloride placebo to maintain blinding. This is a phase III clinical trial with an estimated recruitment start date of November 1, 2025, and an anticipated completion date of December 31, 2027.

The primary objective is to determine the effect of intermediate versus standard dose low-molecular-weight heparin on the incidence of major venous thromboembolism following severe trauma. The primary endpoint is a composite measure consisting of symptomatic deep vein thrombosis, proximal deep vein thrombosis, and pulmonary embolism occurring within 14 days following randomisation. The key secondary endpoint, included in a sequential hierarchical testing procedure, comprises a composite of major venous thromboembolism as defined in the primary endpoint and major bleedings, defined by the need for a haemostatic invasive procedure because of bleeding, the need for interruption of prophylactic enoxaparin for 48 hours or more because of bleeding, or bleeding in a critical organ within 14 days following randomisation. Additional secondary endpoints include major or clinically relevant non-major bleeding as per ISTH definition occurring during or within 48 hours of the last dose of study drug, incidence of major venous thromboembolism and major bleeding at day 30 following randomisation, and death at day 30 following randomisation.

Eligible participants include all adult patients aged 18 years or older admitted to an intensive care unit following trauma with an expected stay exceeding 48 hours and a planned administration of low-molecular-weight heparin. Participants must have affiliation to the French social security system or European health insurance. The maximum treatment period is 14 days. In the intermediate dose group, the maximum daily dose is 8000 IU with a maximum total dose of 112000 IU over the treatment period. In the standard dose group (placebo-controlled arm), the maximum daily dose is 4000 IU with a maximum total dose of 56000 IU over the treatment period.

Participant involvement extends through the treatment period of up to 14 days with follow-up assessments continuing to day 30 following randomisation. Early termination from the study may occur if prophylactic enoxaparin requires interruption for 48 hours or more due to bleeding complications, if a haemostatic invasive procedure becomes necessary because of bleeding, or if other safety concerns arise that necessitate withdrawal from the study intervention.

The experimental medication consists of **LOVENOX** 30,000 IU (300 mg)/3 ml, **solution for injection**, containing **enoxaparin sodium** as the active substance. The pharmaceutical form is a solution for injection administered via **subcutaneous injection**. The maximum daily dose is 8,000 IU international units, with a maximum total dose of 112,000 IU international units over the treatment period. The maximum treatment period is 14 days. Three different formulations of LOVENOX with identical dosing parameters are utilized in this clinical trial.

The **placebo** comparator is designated as PLACEBO_HEPTRAUMA, a solution for injection containing **sodium chloride** as the active substance. This placebo is administered via subcutaneous injection to maintain blinding in this **double-blind randomized controlled trial**. The maximum daily dose for the placebo is 4,000 IU international units, with a maximum total dose of 56,000 IU international units. The maximum treatment period for the placebo is 14 days, identical to the experimental medication.

The trial compares intermediate dose versus standard dose **low-molecular-weight heparin** therapy in severe trauma patients. All investigational products are administered through the subcutaneous route to ensure consistency in drug delivery. The dosing schedule is designed to evaluate the efficacy of different enoxaparin dosing regimens in preventing **venous thromboembolism** in the target population. The trial design incorporates a placebo control arm to establish baseline comparisons for the primary efficacy endpoints.

Efficacy will be assessed through the evaluation of venous thromboembolism and bleeding events following severe trauma. The primary endpoint is a composite measure consisting of symptomatic deep vein thrombosis, proximal deep vein thrombosis, and pulmonary embolism within 14 days following randomisation. The key secondary endpoint, included in a sequential hierarchical testing procedure, comprises a composite of major venous thromboembolism as defined in the primary endpoint and major bleedings, defined by the need for a haemostatic invasive procedure because of bleeding, the need for interruption of prophylactic enoxaparin for at least 48 hours because of bleeding, or bleeding in a critical organ within 14 days following randomisation. Additional secondary endpoints include major or clinically relevant non-major bleeding as per ISTH definition occurring during or within 48 hours of the last dose of study drug, incidence of major venous thromboembolism and major bleeding as per ISTH definition at day 30 following randomisation, and death at day 30 following randomisation.