Evaluation of Apixaban on Thrombin Generation in De Novo Multiple Myeloma and Post-Total Knee Replacement Patients for Thromboembolism Prophylaxis

The primary objective of this study is to compare the **pharmacodynamic** effect of Apixaban, measured by thrombin generation via thrombinography, at peak concentration following a 2.5 mg dose. This comparison is conducted between patients treated for de novo multiple myeloma and those undergoing surgery for total knee replacement. The clinical relevance of this objective lies in understanding the efficacy of Apixaban in different patient populations, which is crucial for optimizing thromboembolism prophylaxis.

Secondary objectives include:

• Comparing the **pharmacokinetics** of Apixaban in the two groups using mass spectrometry.
• Evaluating the evolution of pharmacodynamics through thrombin generation in the presence and absence of thrombomodulin in both groups.
• Modeling the pharmacokinetic-pharmacodynamic relationship in the two groups.
• Assessing the evolution of exposure to Apixaban in patients with multiple myeloma, considering the impact of concomitant treatments and response to treatment, with sampling at the 5th cycle of chemotherapy.

The clinical trial focuses on evaluating the pharmacodynamic effect of **Apixaban** in patients requiring thromboembolism prophylaxis. The study population includes both male and female participants over the age of 18, encompassing individuals with de novo multiple myeloma and those undergoing knee joint replacement with a total prosthesis. Participants are required to be covered by a social security scheme and must provide signed informed consent. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are chemotherapy-naïve for multiple myeloma or are undergoing knee joint replacement, with thromboprophylaxis with Apixaban being recommended for both groups.

The clinical trial is designed to evaluate the **pharmacodynamic** effects of **Apixaban** in patients with de novo multiple myeloma and those undergoing total knee replacement surgery. This study is a randomized, double-blind, controlled trial with an estimated duration from September 2024 to March 2027. The primary objective is to compare the effect of Apixaban on thrombin generation, measured by thrombinography at peak concentration following a 2.5 mg dose. The trial will involve two groups: patients with de novo multiple myeloma and patients undergoing knee joint replacement surgery. The primary endpoint is the endogenous thrombin potential (ETP) measured at peak concentration after administration of Apixaban, with secondary endpoints including Apixaban concentration and pharmacodynamic evolution kinetics.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18, signed informed consent, and specific medical conditions. Follow-up visits will occur at specified intervals to monitor the pharmacokinetic and pharmacodynamic parameters, including blood sample collection at various time points (H0, H2, H6, and H12) post-Apixaban administration. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any adverse events are addressed.

The expected length of participant involvement is approximately 38 weeks, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with study procedures. The trial is categorized as low-intervention, as it does not alter the standard treatment or medical management of patients, aside from additional blood sampling for research purposes. The study aims to provide valuable insights into the pharmacodynamic effects of Apixaban, contributing to improved thromboembolism prophylaxis strategies.

The clinical trial involves the administration of **Apixaban**, a chemical substance, as the experimental medication. The product used is "Apixaban Teva GmbH 2.5 mg film-coated tablet," manufactured by TEVA GMBH. The pharmaceutical form of the medication is a film-coated tablet, and it is administered orally. The dosage for the trial is 2.5 mg per tablet, with a maximum daily dose of 5 mg. The total maximum dose over the treatment period is 190 mg. The treatment period is set for a maximum of 38 days. The primary objective of the trial is to compare the pharmacodynamic effect of Apixaban on thrombin generation in patients with de novo multiple myeloma and those undergoing surgery for total knee replacement.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The trial focuses solely on the effects of Apixaban. Participant compliance with the dosing schedule is crucial, and the administration is monitored to ensure adherence to the prescribed regimen. The trial aims to measure the effect of Apixaban at peak concentration, specifically 2 hours after administration, using thrombinography in peripheral venous blood samples.

Efficacy in this clinical trial will be assessed primarily through the measurement of the **endogenous thrombin potential (ETP)**, which is determined by thrombinography using the MidiCAT method. This primary endpoint will be evaluated at peak concentration following the administration of a 2.5 mg dose of Apixaban. The ETP is expressed as the concentration of active thrombin multiplied by time (nM.min) and will be measured in patients with de novo multiple myeloma and those undergoing total knee replacement surgery. Blood samples for this assessment will be collected two hours after the first dose of Apixaban.

Secondary endpoints include the measurement of Apixaban concentration in ng/mL using mass spectrometry over a 12-hour period post-administration. Additionally, the pharmacodynamic evolution kinetics of thrombin generation will be evaluated using parameters such as ETP (nM/min), Lagtime (min), Time to peak (min), and Thrombin peak (M Thrombin) in the presence and absence of thrombomodulin. These measurements will be taken at timepoints H0, H2, H6, and H12 following Apixaban administration. The study will also involve modeling the pharmacokinetic-pharmacodynamic relationship in each group and evaluating changes in pharmacokinetics and pharmacodynamics after five cycles of chemotherapy, with a possible variation of one cycle, for patients in the de novo multiple myeloma group.