Randomized, Double-Blind, Placebo-Controlled Trial of Epoetin Alfa in Mechanically Ventilated Critically Ill Patients with Traumatic Injury

The primary objective of this study is to evaluate the efficacy of **epoetin alfa** compared to placebo in reducing mortality and severe disability at six months in critically ill patients who have experienced a traumatic injury. This is clinically relevant as it addresses the potential of **epoetin alfa** to improve long-term outcomes in a population at high risk of adverse events following trauma.

Secondary objectives include assessing:

• Mortality rates in the intensive care unit (ICU) and hospital, as well as at 28 days and six months.
• Glasgow Outcome Scale Extended (GOSE) scores at six months.
• Incidence of composite thrombotic events at six months.

The clinical trial involves a total of **1600 participants** who have experienced a **traumatic injury**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants are critically ill trauma patients admitted to the ICU, who are invasively mechanically ventilated and expected to remain in the ICU for at least 48 hours. They must have sustained their primary traumatic injury less than 24 hours prior to enrollment and have a haemoglobin level not exceeding the upper limit of the normal reference range at the treating institution. The trial population was selected based on these criteria, with informed consent obtained from a legal surrogate or enrollment prior to obtaining consent as per legal requirements. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, reflecting the critical health status of the participants.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **epoetin alfa** in reducing mortality and severe disability in critically ill patients following a **traumatic injury**. The trial will involve participants who meet specific inclusion criteria, such as being between 18 to 75 years of age, having experienced a traumatic injury within the last 24 hours, and requiring invasive mechanical ventilation. The study will be conducted over an estimated period from March 29, 2022, to December 31, 2025, with a maximum treatment period of 8 weeks for each participant.

Participants will be randomly assigned to receive either **epoetin alfa** or a placebo, both administered as a **solution for injection in a pre-filled syringe**. The primary endpoint is a combination of mortality and severe disability, defined by a WHODAS 2.0 score of 25% or more, assessed at six months. Secondary endpoints include various mortality rates and the incidence of thrombotic vascular events at six months.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor the participants' health status and response to treatment. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience adverse events, withdraw consent, or if the investigator deems it necessary for their safety.

The expected length of participant involvement is up to 8 weeks, with follow-up assessments extending to six months post-treatment to evaluate long-term outcomes. The trial aims to provide valuable insights into the potential benefits of **epoetin alfa** in improving outcomes for patients with traumatic injuries.

The clinical trial involves the administration of **Epoetin Alfa**, a recombinant form of erythropoietin, which is utilized to stimulate erythropoiesis. The experimental medication is provided in three different formulations, each as a **solution for injection** in a pre-filled syringe. The first formulation is EPREX 40,000 IU/mL, manufactured by Janssen-Cilag, and is authorized under the marketing authorization number 34009 369 925 9 7 in France. The second formulation is Binocrit 40,000 IU/1 mL, produced by Sandoz GmbH, with the marketing authorization number EU/1/07/410/051 in the European Union. The third formulation is Epoetin alfa HEXAL 40,000 IU/1 mL, manufactured by HEXAL AG, with the marketing authorization number EU/1/07/411/051 in Norway. Each formulation is administered via injection, with a maximum daily dose of 1 IU/mL and a total maximum dose of 2 IU/mL, over a treatment period of up to 8 weeks.

In addition to the experimental treatments, a **placebo** is used as a comparator in this double-blind, placebo-controlled trial. The placebo is categorized under the ATC code V07AB, which includes solvents and diluting agents, including irrigating solutions. The placebo is administered in a similar manner to the experimental treatments, ensuring the blinding of the study. The placebo is also provided in a solution form for injection, with a maximum daily dose of 1 mL and a total maximum dose of 2 mL, over the same treatment period of up to 8 weeks.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial aims to evaluate the efficacy of Epoetin Alfa in reducing mortality and severe disability at six months in critically ill trauma patients, compared to the placebo. The study is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.

The efficacy of **epoetin alfa** in the clinical trial will be assessed by evaluating its impact on reducing mortality and severe disability in critically ill trauma patients. The primary endpoint for efficacy is a combination of mortality and severe disability, defined as a WHODAS 2.0 score of 25% or greater, measured at six months post-treatment. Secondary endpoints include six-month mortality, ICU mortality, hospital mortality, 28-day mortality, and the dichotomized extended Glasgow Outcome Score Extended (GOSE) into favorable (greater than 4) and unfavorable (less than 4) outcomes at six months. Additionally, the proportion of participants experiencing composite thrombotic vascular events, such as deep vein thrombosis, pulmonary embolism, myocardial infarction, cardiac arrest, and cerebrovascular events, will be assessed at six months.