Dose Study of Tranexamic Acid in Total Hip Replacement to Reduce Postoperative Hemoglobin Loss. A Phase 2 Randomized Double-blind Monocentric Study. The PRADO study

The primary objective of this study is to evaluate the **dose-response relationship** of intravenous tranexamic acid administration in patients undergoing total hip replacement surgery, specifically focusing on the reduction of perioperative hemoglobin loss. This is clinically relevant as it aims to optimize the dosing of tranexamic acid to minimize blood loss, which can reduce the need for blood transfusions and improve patient outcomes in hip arthroplasty.

Secondary objectives include:

• Evaluating the dose-concentration-response relationship (pharmacokinetic-pharmacodynamic) to better understand the drug's behavior in the body.
• Comparing erythrocyte transfusion requirements between patient groups from the day of surgery (D1) to day 8 (D8), which can provide insights into the effectiveness of tranexamic acid in reducing transfusion needs.
• Comparing the proportion of patients with anemia (hemoglobin less than 10 g/dL) between patient groups from D1 to D8, which is important for assessing the impact on anemia management.
• Comparing the occurrence of symptomatic thromboembolic events, convulsive seizures, or death until D8 between groups, to evaluate the safety profile of the treatment.
• Measuring the rate of complications such as venous/arterial thromboembolism and hematoma requiring repeat surgery or associated with infection at D45 ± 1 week, to assess long-term safety and complication rates.

The clinical trial involves participants diagnosed with **arthropathy of the hip**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. The trial does not involve a vulnerable population. Participants were selected based on the requirement for primary hip arthroplasty within a three-month period, and informed consent was obtained from the patient, a family member, or a support person. The sponsor has not provided information regarding the total number of participants. No specific lifestyle considerations such as diet or physical activity are mentioned in the trial data.

The clinical trial is designed to evaluate the **dose-response relationship** of intravenous **tranexamic acid** administration in patients undergoing total hip arthroplasty, specifically focusing on the reduction of perioperative hemoglobin loss. This is a Phase 2, randomized, double-blind, monocentric study. The trial is expected to commence recruitment on July 1, 2023, and conclude by December 31, 2026. Participants will be randomly assigned to receive either the investigational product or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study.

The study will involve several key visits. The initial visit, known as the inclusion or screening visit, will determine participant eligibility based on criteria such as the requirement for primary hip arthroplasty within the last three months and obtaining informed consent. Following the screening, eligible participants will be enrolled and randomized. The primary endpoint of the study is the percentage decrease in hemoglobin levels during the perioperative period, requiring blood samples before surgery and on the eighth postoperative day. Secondary endpoints include pharmacokinetic and pharmacodynamic assessments of tranexamic acid, the incidence of allogenic red blood cell transfusion, severe anemia, and symptomatic thrombotic events.

Participants will be involved in the study for a maximum treatment period of 38 days, with the possibility of early termination if adverse events occur or if the participant withdraws consent. Follow-up visits will be scheduled to monitor the participants' health status and collect necessary data, with a final end-of-study visit to assess the overall outcomes and any long-term effects. The study aims to provide valuable insights into the efficacy and safety of tranexamic acid in reducing postoperative hemoglobin loss in patients with **arthropathy of the hip** undergoing surgery.

The clinical trial involves the administration of **APIXABAN**, a chemical active substance, in the form of a film-coated tablet. The pharmaceutical form is designed for oral administration. The maximum daily dose of APIXABAN is 5 mg, with a total maximum dose of 190 mg over a treatment period of 38 days. The administration schedule is structured to ensure compliance with the dosing regimen, and participant adherence is monitored throughout the trial.

**TRANEXAMIC ACID** is utilized in the study as a solution for injection, provided by LABORATOIRE AGUETTANT. The active substance is chemically derived and is administered via infusion. The maximum daily and total dose is 3000 mg, with a treatment period limited to 1 day. The product is not compliant with the marketing authorization dose, and this deviation is documented. The administration is conducted under controlled conditions to evaluate its efficacy in reducing perioperative hemoglobin loss during total hip replacement surgery.

**SODIUM CHLORIDE** is employed as a placebo in the form of a solution for infusion, also supplied by LABORATOIRE AGUETTANT. The chemical substance is administered via infusion, with a maximum daily and total dose of 3000 mg, over a treatment period of 1 day. This placebo is used to maintain the double-blind nature of the study, ensuring unbiased results in the evaluation of the primary treatment's efficacy.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage of **haemoglobin** decrease in the perioperative period, which will be evaluated by sampling haemoglobin levels before surgery and on the eighth postoperative day. Secondary endpoints include several measures: the pharmacokinetics of tranexamic acid will be assessed by sampling tranexamic blood concentration, while pharmacodynamics will be evaluated through D-Dimer levels. The percentage of patients receiving at least one allogenic red blood cell unit transfusion in the perioperative period will also be measured. Additionally, the incidence of severe anaemia, defined as haemoglobin levels below 10 grams per deciliter, will be recorded. The trial will also monitor the incidence of symptomatic thrombotic events and death, using a combined criteria of venous events (deep venous thrombosis or pulmonary embolism), arterial events (acute coronary syndrome, stroke, or peripheral arterial thrombosis), and death. Furthermore, at day 45 ± 1 week, the incidence of complications such as venous/arterial thromboembolism, hematoma requiring repeat surgery, or associated infections will be measured.